Article Type : Review Article
Authors : Undisa R, Chemtai AK, Ndede I and Diero LO4
Keywords : HIV-1; Persistent Low-level viremia; Combination antiretroviral therapy; Interleukin-17; Interleukin-10; Interferon gamma gamma; Transforming growth factor beta
HIV-1 low level viremia is a consequence
of virologic failure and has been shown to be caused by dysregulated cytokine
responses in HIV-1 cART patients. Very little has been done to elucidate the
level of IL-17, IFN-?, IL-10 and TGF-?in HIV-1 patient on cART in Kenya.
Compared to genotypic and phenotypic tests, cytokine assays are cheaper and so
employing the use of IL-17, IFN-?, IL-10 and TGF-? may offer one of the
solutions to prediction of low-level viremia in HIV-1 cART patients, as these
cytokines may be key in development of therapies to minimize low level viremia
in HIV-1 patients on cART. This review summarizes the latest understanding of
pro-inflammatory (IL-17, IFN-?) and anti-inflammatory (IL-10, TGF-?) cytokine
activity in peripheral blood of HIV-1 patients, as potential predictors of
low-level viremia, and virologic failure in HIV-1 patients on cART, and gives
proposals on mechanisms to develop therapies based on these cytokines, to be
used in minimizing low level viremia occurrence.
Combination antiretroviral therapy (cART) is meant to
suppress and maintain viral load (VL) in human immunodeficiency virus-1 (HIV-1)
patients at lowest detectable levels using the conventional viral load testing
platforms. After periods of suppression, patients on cART have often reverted
from viral suppression to viremia [1]. Viremia in HIV-1 patients on cART may
lead to development of HIV-1 drug resistant mutants and has been associated
with virological failure, and this has a consequence of morbidity and mortality
in the patients. Cytokines dysregulation could exacerbate persistent low-level
viremia development and subsequent virologic failure in HIV-1 patients on
HAART. To gain insight into the immunological predictors’ persistent low-level
viremia in HIV-1 patients on cART, the levels of IL-17, IFN-?, IL-10 and TGF-?
in HIV-1 patients on first line with low level viremia and cART adherent may be
explored to relate the level of the cytokines to HIV-1 persistent low-level
viremia, virologic failure, and disease progression. Combination antiretroviral
therapy (cART), previously called highly active antiretroviral therapy (HAART)
suppresses human immunodeficiency virus-1 viral replication to undetectable
levels, delays development of mutant strains, and improves immunological status
of human immunodeficiency virus-1 (HIV-1) patients [2,3]. An important global
sustainable goal geared towards ending the human immunodeficiency virus /
acquired immunodeficiency syndrome (HIV/AIDs) epidemic by 2030 is achievable through
strategies which include attaining viral load suppression in over 95% human
immunodeficiency virus-1 patients on combination antiretroviral therapy [4]. In
efficiently controlling human immunodeficiency virus-1 progression, combination
antiretroviral therapy has transformed the pandemic into a manageable chronic
disease, however eradication remains an objective due to virus persistence and
rebound [5]. Viral load is reported to drop when patients are introduced to and
successfully respond to combination antiretroviral therapy [6]. Studies have
shown that, despite viral suppression, low level viremia still occurs in human
immunodeficiency virus-1 patients on combination antiretroviral therapy [7,8].
Persistent low level viremia has been associated with viral genotype
resistance, adherence difficulties, acquired immunodeficiency syndrome events,
and virologic failure [9,10].
Cytokines
Cytokines are proteins secreted by cells of the body
to act on other cells, or on the cells that produced them through regulation
and influencing of immune response [11]. An imbalance in T helper 1 (Th1) and T
helper 2 (Th2) cytokines in human immunodeficiency virus-1 patients on
combination antiretroviral therapy could provide some of the answers revolving
around virologic rebound and low level viremia (Ma et al., 2019a). There is
need for insight into human immunodeficiency virus-1 -immune system interaction
in the wake of persistent low-level viremia, with the objective of maintaining
viral suppression and minimizing low level viremia in human immunodeficiency
virus-1 patients on combination antiretroviral therapy, thereby contributing to
the advancing field of immunology. Characterization of cytokines that
constitute human immunodeficiency virus-1 reservoir maintenance is important in
pathogenesis of human immunodeficiency virus-1, as cytokines could be used in
monitoring of disease prognosis during therapy, to maintain the viral load at
lowest detectable levels, which would minimize virologic failure. To add to
this, cytokines immunotherapy could be a promising therapeutic option in human
immunodeficiency virus-1 patients on combination antiretroviral therapy (cART).
The cytokines, while working in cell signalling, mediate cell-to- cell
interaction in higher organisms, through forming complex networks which are
altered in infections such as human immunodeficiency virus-1 [12]. Being
modifiers and effectors of innate and adaptive immune system inflammation,
cytokines are responsible for intercellular communication and immune regulation
[13]. These proteins are produced by T lymphocytes, which are the major
effectors in cellular immunity, and work by mediating inflammation and
regulating other immune cells [14]. The multifaceted interaction of cytokines
in viral infections has been shown to be involved in disease pathogenesis [15].
Cytokines, are biomarkers of inflammation and may be used in monitoring disease
progress and also for therapy. The various immune biomarkers found in human
immunodeficiency virus-1 infection have been associated with disease
progression, and during the infection a number of cytokines including
interferon gamma are produced.
Cytokines are categorized into pro-inflammatory and
anti-inflammatory, and their release leads to the release and production of other
cytokines, bringing out the “cytokine storm” phenomenon. It has been shown
that, in human immunodeficiency virus-1 infection, various immune biomarkers
have been associated with disease progression. T cell activation and biomarkers
of inflammation are thought to predict human immunodeficiency virus-1 disease
progression, as high levels have been found in peak viremia [16]. While
pro-inflammatory cytokines are against infection and injury, anti-inflammatory
cytokines limit the injurious effects of pro?inflammatory cytokines [17]. There
have been suggestions that the immunologic profiles and cytokine expression in
human immunodeficiency virus-1 patients is more proinflammatory than
immunoregulatory [18]. In acute human immunodeficiency virus-1 infection, it
has been shown that, cytokine storm that ensues, is followed by the production
of immunoregulatory cytokines. Additionally, Human immunodeficiency virus-1
(HIV-1) infection has been shown to lead to upregulation of various cytokines,
and the persistence has been demonstrated even in combination antiretroviral
therapy inhibition of viral replication. In human immunodeficiency virus-1
infection, there is a general tendency of increased cytokine levels due to
progression of immunodeficiency, and when combination antiretroviral therapy
has not been initiated and the trend is reversed on combination antiretroviral
therapy initiation [19]. The cytokine suppresses the regulator of viral
transcription, and exhibit non-cytolytic antiviral activity [20]. It has been
suggested that, in early stages of human immunodeficiency virus-1 infection,
Th1 response dominates, while during chronic infection, Th2 response is
predominant, leading to increased production of interleukin 10, among other
immunosuppressive cytokines [21]. Human immunodeficiency virus-1 (HIV-1)
disease progression leads to enhanced secretion of pro-inflammatory cytokines,
as several studies have revealed a correlation between the cytokines, with
human immunodeficiency virus-1 viral load [22]. As ealier noted, cytokines
which increase over the course of chronic human immunodeficiency virus-1
infection include the anti-inflammatory proteins such as interleukin 10 and
transforming growth factor -Beta. It has
been suggested that, various cytokines release is a characteristic of increased
viral replication [23]. Similarly, both proinflammatory and immunosuppressive
cytokines have been shown to inhibit viral replication by favouring human
immunodeficiency virus-1 latency [24], as the increased production of pro
inflammatory cytokines is an important facet of human immunodeficiency virus-1
induced chronic immune activation.
Interleukin-17
Interleukin-17 is a cytokine produced by cells of
immunity, notably Th17 cells, gamma delta T
cells, natural killer T cells (NKT cells), Cell differentiation antigen
8 T cells, neutrophils, natural killer cells (NK cells), , mast cells, and
microglia. As interleukin-17 is a proinflammatory cytokine which mediates
immunopathology and inflammation, this pro-inflammatory cytokine as produced by
Th17 cells recruits neutrophils and monocytes to the site of infection, and its
activation leads to downstream of chemokines and cytokines such as MCP-1,
IL-21, IL-8, IL-6 and IL-1 [25]. In a study done by elevated interleukin-17 was
associated with human immunodeficiency virus-1 transmission [26].
Interleukin-17 has been shown to play a critical host immune response
protective role in infections such as viral, bacterial, and fungi. In
maintaining tissue integrity, interleukin-17
plays a pivotal role particularly at epithelial barrier cites, via
generating protective immune responses to microbes Additionally, the
pro-inflammatory function exerted by interleukin-17 plays a critical role in
inflammatory conditions, occasioned by stress proteins, microbial metabolites,
and pathogen Associated Molecular Patterns (PAMPs) [27]. Alongside a myriad of
inflammatory cytokines, interleukin 17 has been found to be a foremost
proinflammatory cytokine which plays a salient role in generation of a protective
immune response [28]. Interleukin 17 has further been thought to characterize
human immunodeficiency virus-1 disease severity. Interleukin 17 and concerted
actions of other proinflammatory and immunoregulatory cytokines, by which the
final immunological response and severity of the viral infection is depended.
This may partially explain the pathogenic and protective functions of
interleukin 17, in disparate settings of inflammation.
While interleukin 17 (IL-17) has been shown to play a pivotal role against viruses thorough regulation of
the immune responses, it is worthwhile noting that some studies have found
reduced levels of interleukin 17 in human immunodeficiency virus-1 patients on
combination antiretroviral therapy [29]. None the less, contradicting findings
have found higher levels of interleukin 17 in human immunodeficiency virus-1
patients with viral loads less than 50 copies/ml [30], signifying there could
still be levels of inflammation even in patients responding well to combination
antiretroviral therapy. Other known functions of interleukin 17 include the
promotion of neutrophil migration to a site of inflammation and playing a
crucial protective role during intestinal inflammation. Additionally,
Interleukin -17 also plays a significant role in promoting cytotoxic T – cell
activity and enhancing Th1 immune
response, modulating antiviral B-cell activities, inducing protective
inflammatory responses. Interleukin 17 has been known to stimulate fibroblasts
into the secretion of other cytokines such as Prostaglandin E2 (PGE2),
granulocyte-colony stimulating factor (G-CSF), IL-6, and IL-8 [31]. Some
studies have postulated that Interleukin -17 is produced in human
immunodeficiency virus-1 combination antiretroviral therapy naïve patients,
with undetectable viral load Interleukin 17 has also been indicated as a
therapeutic target and biomarker in sepsis.
In limiting viral infection-induced pathology,
interleukin 17 mediates protective immune responses, inhibits detrimental
inflammations, and contributes to maintenance of tissue integrity. Interleukin-17 has protective effects against
viruses, bacteria, and parasitic infections, and high levels could predict a
greater risk of sepsis progression. Studies have shown an increasing human
immunodeficiency virus-1 replication association with interleukin 17
inflammatory activities. The potential to recruit phagocytes at high notch is
what makes interleukin 17 response to be potentially dangerous in the midst of
the many benefits. Interleukin 17 has been thought to play an important
function in repair, pathology, and barrier surface protection. In response to
invading virus, inducing excessive neutrophil migration and activation,
antagonizing development of T regulatory cells, inducing Th2 immune responses,
and promoting fibrosis development, are some of the mechanisms used by
interleukin 17 in contributing to tissue damage during viral infections.
Although reported mostly as associated with immunopathology, interleukin 17
plays a vital role in host defense. The successful operation of interleukin 17
in immunity arises partly from the synergistic activities with other factors,
the role as a counterpart of interferon gamma, and the self-sustaining feedback
loop.
It has been suggested that, in human immunodeficiency
virus-1 infection, high levels of interleukin 17 correlate with high viral load
[32] as higher interleukin 17 cytokine levels have been found in uncontrolled
human immunodeficiency virus-1 infected patients. Through induction of
innate-like acute immune defenses, such as chemokines, interleukin 17 signals
mostly in non-hematopoietic cells. Additionally, interleukin 17 acts through
increasing serum concentrations for GM-CSF and G-CSF and via acute phase
proteins, to hasten the development of other required subsets of immune cells
such as macrophages and neutrophils, over eosinophils and basophils. Generally,
interleukin 17 is thought to have the main function of protection of tissues
against the invasion of microbes, through the swift recruitment of phagocytes
to the site of infection. This further kicks off antimicrobial factor
induction, as well as maintaining recruited cells, and enhancing access to
tissues. When chronically directed to inappropriate targets, interleukin 17
through the pro-inflammatory effect contribute to pathogenic inflammation.
Thus, interleukin 17 centrally orchestrates immunity in humoral and cellular
immunity in line with IL-4 and IL-13, and interferon gamma respectively. During
functioning, interleukin 17 can recruit a large number of polymorph nuclear
cells, and has the capability of maintaining these population of cells at the
sites of infection. In the course of various infections, interleukin 17 is
produced by lymphoid cells which include Tc17, gamma delta T cells, and Th17 cells,
in the course of varied infections.
Interferon Gamma(IFN-?), as produced by leukocytes,
was discovered in 1965 by Fredrick Wheelock, as the only member of the type II
interferon family as a soluble macromolecule antiviral factor, with strong
pleiotropic immunomodulatory effects on innate and adaptive [33]. This
pro-inflammatory cytokine has been shown to be produced mostly by T cells and
natural killer cells, and works by increasing neutrophil and monocyte function,
macrophage activation, has antiviral activities, and works on MHC-1 and II
expression on cells. High levels of interferon gamma were associated with human
immunodeficiency virus-1 disease progression. It has been well stipulated that
interferon gamma, whose original function is natural antiviral activity may be
effective in viral infections and disseminated multi-organ invasion. Studies
have reported increased interferon gamma in successful combination
antiretroviral therapy. Interferon gamma works by mediating the innate and
adaptive immune responses. Interferon gamma is among the cytokines that
characterize human immunodeficiency virus-1 disease severity. Interferon gamma
is also known for influencing transcriptional regulation of a number of genes,
as some studies have reported extreme susceptibility to infectious diseases
when there is a disruption of interferon gamma gene or it’s receptor. During a
cytokine storm, lysis of immune cells or T cell activation triggers interferon
gamma release, which leads to immune cells activation, and subsequent
pro-inflammatory cytokine release [34]. Interferons are important in control of
various virus infections. As a signature cytokine in activated T cells, interferon
gamma is the most potent macrophage activator, in addition to the modulation of
both adaptive and innate immune networks. Interferon gamma has been reported as
a key driver of cellular immunity, and orchestrates milliard protective
functions in the process of heightening of immune responses in infections.
Interferon gamma induces antigen specific regulatory B cells and T cells, which
act in a counter-regulatory fashion in an immune reaction, leading to
prevention and control of excess immune responses such as the occurrence in a
cytokine storm that may be fatal. Patients with chronic human immunodeficiency
virus-1 infection display CD4+ T cells, with upregulated interferon stimulated
genes. Interferon gamma is among the cytokines thought to predict human
immunodeficiency virus-1 disease progression. The functioning of interferon
gamma is through enhancing of increasing leukocyte infiltration, affecting
cellular apoptosis and proliferation. Persistent interferon signalling has been
found in pathogenic primates. The expression of many interferon regulated
genesis is a characteristic of interferon response to human immunodeficiency
virus-1 infection, and leads to an anti-viral state is establishment in both
bystander and infected cells [35]. Various roles are played by interferon gamma
in human immunodeficiency virus-1 pathogenesis (Roff et al., 2014). As
stipulated earlier, while cells involved in the secretion of interferon gamma
include activated CD4 T cells and Cell differentiation antigen 8 T cells, natural
killer cells (NK cells), gamma delta T cells, natural killer T cells( NKT
cells) , B cells, monocytes, dendritic cells, and macrophages. The cytokine has
been found to be produced from the leukocytes upon stimulation with a mitogenic
plant lectin, phytohemagglutinin, and known to activate innate cell-mediated
immunity, and stimulate adaptive antigen-specific immunity [36]. Some studies
have postulated that interferon gamma is produced in human immunodeficiency
virus-1 combination antiretroviral therapy naïve patients, with undetectable
viral load. Interferon gamma in human immunodeficiency virus-1 infection is
detected early, at the acute phase, and remains continually produced throughout
the course of infection. Some of the advantages of interferon gamma as a
therapeutic agent are: It’s effectiveness in viral infections has strongly been
predicted, as a virus-specific antiviral therapeutics agent, it can be used in
epidemics, and in new viral infections. The fact that interferon gamma is able
to enhance natural killer cell and cytotoxic T cell activity against human
immunodeficiency virus-1 infected cells signifies the relevance of this
cytokine in the control of human immunodeficiency virus-1 replication.
Interferon gamma (IFN-?) can through antigen
presentation cells, amplify antigen presentation by cognate T-cell interaction,
induce antiviral responses, and increase Reactive Nitrogen Intermediates (RNIs)
and Reactive Oxygen Species (ROS). For viral infections, interferon gamma is
used as a therapeutic agent, as it interferes with viral multiplication,
eliciting potent anti-viral activity. The strong antiviral activities induced
by interferons makes them a primary actor in pathogen defense. As a regulator
of host immune response to a number of microbes, Interferon gamma has been
shown to be involved in human immunodeficiency virus-1 pathogenesis.
Additionally, interferon gamma has been shown to confer antiviral state through
modulation of T cell and B cell differentiation and maturation, and can also
activate local immune cells such as dendritic cells. It has been shown that,
interruption of antiretroviral therapy predicts virologic rebound in human
immunodeficiency virus-1 patients through the expression of type I
interferon-associated genes. Interferon gamma activities revolve around immune
modulation, proinflammation, and immune activation. During active infection,
high levels of interferon gamma are produced, and acts on the regulation of
antigen presentation by APCs, and the induction of class switching in B cells.
Interferon gamma proinflammatory activities involve enhancing host immune
responses through activation of phagocytic cells leading to oxidative burst
stimulation and release of degradative enzymes. A lack of, or deficiency in
interferon gamma secretion may lead to death as a result of susceptibility to
infectious diseases. In early viral infections, pattern recognition receptors
(PRR) engagement is triggered after recognition of pathogen associated
molecular patterns (PAMPs), or danger associated molecular patterns
(DAMPs). Molecular pattern recognition
initiates antiviral state in antigen presenting cells and the production of
interferon gamma, which triggers innate immune response [37]. In addition to
the induction of the maturation of macrophages toward a proinflammatory
phenotype and antigen presentation, activation of macrophages and neutrophils
diapedesis to the site of infection is promoted by interferon gamma. A study done by revealed elevated levels of
serum IFN? in human immunodeficiency virus-1 patients prior to treatment with
combination antiretroviral therapy, and decreasing levels with the initiation
of combination antiretroviral therapy, while other studies have however
demonstrated higher levels of interferon gamma even after combination
antiretroviral therapy initiation, signifying that IFN? may either prevent or
augment the pathogenesis of human immunodeficiency virus-1.
The proinflammatory antiviral response and immune
regulation has made interferon gamma a potential biomarker that is used in
immune competence and antiviral response evaluation in human immunodeficiency
virus-1 patients. It has been shown that, in playing the key role in innate and
adaptive immune responses, interferon gamma (IFN-?) promotes differentiation of
naive CD4+ cells into effector Th1 T cells leading to the antiviral activities,
and immunity against intracellular infections. Interferon gamma (IFN-?) also
facilitates leucocyte migration, and the growth and maturation of other cells
types such as glial cells, mesenchymal cells, and dendritic cells. In
interfering with viral life cycle, interferon gamma inhibits virus entry, both
at the extracellular and intracellular stages, inhibits viral replication, and
disrupts gene expression, preventing translation. Interferon gamma has been
shown to steadily increase throughout the acute stage of human immunodeficiency
virus-1 infection. There is a postulation that interferon gamma levels decrease
during chronic human immunodeficiency virus-1 infection to levels similar to
healthy individuals. From findings of recent studies, human immunodeficiency
virus-1 infection has been associated with the induction of interferon gamma
response. Elevated levels of interferon gamma in human immunodeficiency virus-1
patients on combination antiretroviral therapy have been suggested to either
control or enhance human immunodeficiency virus-1 disease, based on the human
immunodeficiency virus-1 infection clinical stage. Several studies have found
high levels of interferon gamma as sustained in human immunodeficiency virus-1
patients despite combination antiretroviral therapy, and with the high levels,
there is a lower rate of comorbidities.
Interferon gamma (IFN-?) plays a critical role in
human immunodeficiency virus-1 pathogenesis through enhancing host resistance
to infection, as evidenced by study findings in which higher levels of
interferon gamma were found in human immunodeficiency virus-1 combination
antiretroviral therapy naïve patients [38] and the levels remain high in human
immunodeficiency virus-1 patients on combination antiretroviral therapy. On the
contrary, in their study observed reduced interferon gamma levels in both
combination antiretroviral therapy naïve as well as combination antiretroviral
therapy experienced human immunodeficiency virus-1 patients, with a positive
correlation with CD4 count, and a negative correlation with human
immunodeficiency virus-1 viral load. Additional studies have reported, increase
in interferon gamma in successful combination antiretroviral therapy [39],
while levels are reduced before therapy and 12 months into therapy, [40]
signifying that the cytokine response may be un affected in combination
antiretroviral therapy, probably due to residual virus in immune sanctuaries,
which necessitates persistent immune activation. There is an increasing
suggestion that interferon gamma protects the host against viral infections, by
inhibiting viral entry at intracellular and extracellular levels [41].
Furthermore, low viral load has been shown to correlate positively with
interferon gamma human immunodeficiency virus-1 specific CD4+ T cells.
Interferon gamma steadily increases in acute stage of human immunodeficiency
virus-1 infection, and levels decline in chronic disease, to levels similar to
those in healthy individuals. It has been postulated that Immunologic profiles,
and cytokine expression is proinflammatory than immunoregulatory in human
immunodeficiency virus-1 patients. Also, infection with human immunodeficiency
virus-1 results in antigen presentation modification in dendritic cells and
macrophages, leading to anergic state in T helper cells specific to human
immunodeficiency virus-1.
Being a proinflammatory cytokine and in regulator of
cytotoxic T cell response , interferon gamma, through direct activation of
phagocytic cells triggers oxidative burst, and the release of degradative enzymes as synergy
with other cytokines ensues [42]. Interferon gamma has been known to prevent
viral replication and promotion of innate and adaptive immunity and so the
proinflammatory antiviral response and immune regulation characteristics
upgrades this cytokine as a biomarker for consideration in evaluating antiviral
response and immune competence in human immunodeficiency virus-1 infection.
Interferon gamma inducts the secretion of proinflammatory cytokines by
fibroblasts, epithelial cells, and endothelial cells and since it is produced
in cytokine storm in acute stage of human immunodeficiency virus-1 infection,
this cytokine is thought to affect the development of cytotoxic T lymphocyte
functions in controlling human immunodeficiency virus-1 viral load. As human
immunodeficiency virus-1 efficiently replicates in tissues and triggers the
upregulation of a variety of cytokines, such as IFN-gamma, higher levels of
interferon gamma have been found in combination antiretroviral therapy
non-responders, and in combination antiretroviral therapy patients, a transient
viremia of more than 1000copies/ml has been associated with high levels of this
cytokine [43]. It may be plausible to note that, since some studies reported
high levels of IFN ? in combination antiretroviral therapy patients, as well as
a number of patients in the same study recording low levels, the probable
suggestion to this observation could be that, this may be attributed to genetic
characteristics of human immunodeficiency virus-1 and individual differences in
immune responses against human immunodeficiency virus-1, and no other
confounding clinical events.
Interleukin-10
(IL-10)
Interleukin-10, an anti-inflammatory cytokine is a
cytokine synthesis inhibitory factor (CSIF), which works by attenuating T cells
and Th17 cell response through regulatory CD4+ T cells. Pro inflammatory
cytokines have been shown to impact the antigen sensitivity of Cell
differentiation antigen 8+ T cells, while the interleukin 10, which is produced
during chronic infection was associated with reduced Cell differentiation
antigen 8+ T cell antigen sensitivity during the establishment of chronic
infection. Additionally, this cytokine is thought to regulate immune
homeostasis in health and disease. It is produced by T cells, B cells, and
macrophages, among other immune cells, and inhibits mononuclear cell function
and cytokine production [44,45]. This study found high levels of interleukin 10
in human immunodeficiency virus-1 patients with persistent low level viremia
compared to interleukin 10 level in human immunodeficiency virus-1 suppressed
patients, which agrees with the findings by Gorenec and team in which the levels
of interleukin 10 were high in human immunodeficiency virus-1 patients on
antiretroviral therapy, during the stage of chronic human immunodeficiency
virus-1 infection. Threshold for CD8+ T cells activation is increased directly
by interleukin 10. Additionally, the signalling of interleukin 10 inhibits Th1
cytokines production, and it stimulates Th2 cytokine production. Interleukin 10
was associated with seroconversion in human immunodeficiency virus-1 patients.
Immunoregulatory cytokine interleukin 10 facilitates the early events of viral
persistence. In the anti-inflammatory environment, high levels of interleukin
10 constrains the proliferative capacity of Th1 cells, and suppresses pro
inflammatory responses which are meant to clear infection. Some studies have
found that interleukin 10 is produced in human immune deficiency virus-1
combination antiretroviral therapy naïve patients, with undetectable viral
load. It has been reported that, CD8+ T cells antigen sensitivity is decreased
in chronic infection, and is directly mediated by interleukin 10. Interleukin
modulated Co-inhibitory receptors expression, Immune metabolism, Tfl
frequencies, gene signatures and proteins associated to cell survival, and
maintenance of memory T cells, and this is associated with human
immunodeficiency virus-1 reservoir persistence. Additionally, there are
however, latently infected long lived memory T cells which persist, and
therefore the residual virus prevents the eradication of the infected cells
[46]. It is now postulated that, reservoir establishment and persistence in
human immunodeficiency virus-1 patients on combination antiretroviral therapy
is contributed to by interleukin 10. Interleukin 10 characterizes human
immunodeficiency virus-1 disease severity. Encoded by interleukin 10 gene in
humans, interleukin -10 has been shown to be a key immunoregulatory cytokine.
In inhibiting immune responses, interleukin 10 works by upregulating membrane
suppressor molecules such as PD-L1, and PD-1 expression, leading to immune response
activation suppression, through shifting inflammatory to anti-inflammatory
immunity.
Interleukin 10 has also been shown to impair the
capacity of TCR signal transduction of CD8+ T cells. For a strong and
functional and proliferative response, T cell activation should ensue in
organized process which involves three signals comprised of recognition of
antigen, through T cell receptor of professional antigen presentation cell
(APC) presented respective cognate antigen, co-stimulation receptor where the T
cells bind to their respective ligand, and the termination signal, which comes
later as immune response effector phase, followed by elimination of the
pathogen. The Mgat5, which is a glycosyltransferase which enhances glycan
branching on glycoproteins surface is induced by interleukin 10. Being an
immunosuppressive cytokine, interleukin 10 signals through signal transducer
and activator of transcription (STAT3) in regulation of T follicular helper
germinal centre formation, and cell differentiation. Interleukin 10 directly
restricts CD8+ T cells activation function through a regulatory loop in chronic
viral infection such as human immunodeficiency virus-1 infection by modifying
cell surface glycosylation. As seen earlier, In T cell exhaustion interleukin 10
is also involved, and this is quite different for chronic activation, as T cell
persistent exposure to constant antigen leads to T-cell exhaustion. The
capacity of CD8+ T cells to develop effector functions in low level antigen
also called functional avidity or antigen sensitivity is dependent on efficient
pathogen control. This happens particularly through inhibiting of the
activation and maturation of innate immune cells such as macrophages, natural
killer cells, and dendritic cells, and on the other hand, expanding the t
regulatory cells, resulting to disease persistence. Impairment of CD8+ T cells
function has been shown to be maintained by residual human immunodeficiency
virus-1 replication, which enables the virus to persist even in combination
antiretroviral therapy [47]. It has been postulated that suboptimal immune
control of infections such as human immunodeficiency virus-1 ensues in T-cell
exhaustion, interleukin 10 induction plays an important role in viral
persistence establishment.
While interleukin 10 is produced by T regs as part of
response by the body to chronic infection established by upregulation of
pro-inflammatory cytokines, this critical component of in the immunosuppression
network, is required to dampen the activities of proinflammatory cytokines
after pathogen encounter. Additionally, In human immunodeficiency virus-1
infection, high levels of interleukin 10 coincides with chronic disease
progression, thus interleukin 10 induction features more in chronic infections.
It has been reported by some studies that, there is a correlation between human
immunodeficiency virus-1 reservoirs in human immunodeficiency virus-1 patients
on combination antiretroviral therapy with interleukin 10 levels, and both
transforming growth factor beta and interleukin 10 contribute to the
immunosuppressive function of T regulatory cells. In cases where combination
antiretroviral therapy is interrupted, viral rebound occurs. Clonal expansion
takes place in human immunodeficiency virus-1 infected cells, and the clonally
expanded cells increase with time. It has been postulated that, more than 50%
of the clonally expanded cells are maintained through latent reservoirs. Viral
rebound is contributed to by the human immunodeficiency virus-1 infected
clonally expanding cells. While combined antiretroviral therapy (cART) reduces
human immunodeficiency virus-1 transmission, maintains a good state of health,
and suppresses human immunodeficiency virus-1 multiplication, it has been
suggested that persistent virus leads to T cell exhaustion which is albeit
established early in infection, and is a huge barrier to immune control of
human immunodeficiency virus-1, greatly hindering the elimination of the virus.
As such, there is a very fragile balance between progressive T cell exhaustion,
and T cell mediated virus control. It is plausible to note that, starting
combination antiretroviral therapy as soon as possible after diagnosis can
reduce viral load to undetectable levels, and in the process restore
immunological function.
Ideally, studies have reported that, when combination
antiretroviral therapy is initiated, a greater number of human immunodeficiency
virus-1 patients have a reduction in human immunodeficiency virus-1 viral load.
Human immunodeficiency virus-1 affects the CD4 receptors on immune cells
leading to improper functioning of the immune system, however, it has been well
articulated that so far, combination antiretroviral therapy only reduces viral
replication, but does not cure human immunodeficiency virus-1. In absence of
effective therapy, inflammation characteristic of human immunodeficiency
virus-1 infection ensues, and it is associated with immune cells changes,
failure of immune reconstitution under combination antiretroviral therapy, a
decrease in antiviral response, and a damage to organs. Interleukin 10 has been
shown to promote the differentiation of CD4+ T cells into a Th2 phenotype, and
increased values have been found in human immunodeficiency virus-1 infection.
The formation of galectin 3-mediated membrane lattice was promoted by increased
CD8+ T cell N-glycan branching, and restricted key glycoprotein and so
increasing T cell activation required antigenic threshold. The serum levels of
interleukin 10, which is a prototypical anti-inflammatory cytokine plays the
immunosuppressive role , and its serum levels are associated with high viral
load, and human immunodeficiency virus-1 progression, and levels are decreased
in effective combination antiretroviral therapy. Combination antiretroviral
therapy decreased the level of interleukin 10. As reported earlier, Low level
viremia of 500-999 copies /ml was associated with virologic failure [48]. Some
studies have suggested that viral suppression was found in human
immunodeficiency virus-1 combination antiretroviral therapy suppressed patients
for a couple of years, and the improper immune activation has been associated
with development of low-level viremia.
In the course of controlling and elimination of
foreign substances, activated T cells may inflict irreparable damage to target
cells. Though it is produced by regulatory CD4+T cells, interleukin-10 is
produced by other cells that include macrophages, dentritic cells, natural
killer cells, monocytes, and neutrophils. Induced toll-like receptor (TLR)
stimulated B cell activation suppression occurs when interleukin 10 and
transforming growth factor beta work in synergy. Anti?inflammatory cytokines
are immunoregulatory inhibitors of excess inflammatory response resulting from
pro?inflammatory cytokines. During it’s functioning, interleukin-10 suppresses
innate and adaptive immunity, and is produced by a variety of cells white blood
cells. Interleukin-10 is elicited as an immunosuppressive cytokine in innate
immune responses to viral infections and other pathogens and protects the
tissues against the effects of inflammatory responses due to infection. Being a
multifunctional cytokine in viral infections, including human immunodeficiency
virus-1 infection, interleukin 10 plays a role in T cell impairment of function
in persistent viral infections and its blockade leads to enhanced viral
control. Interleukin 10 limits high inflammation, as the cytokine balances
proinflammation induced by pathogen associated molecular patterns (PAMPs) and
danger associated molecular patterns (DAMPs). Cellular immune responses and
antigen presentation are inhibited by interleukin 10 in human immunodeficiency
virus-1 infection by reducing IL-12 and IL-2 production leading to an
immunoregulatory state induction in macrophages and dentritic cells. Production
of proinflammatory cytokines and chemokines is restricted by interleukin 10,
thereby preventing Th1 differentiation. On innate immune cells inflammatory
activities, interleukin-10 represses phagocytosis, antigen expression, and
release of immune mediators. Interleukin 10 as a regulatory cytokine balances
the immune response through blocking exaggerated T cell response, by binding to
the inhibitory receptors. High levels of interleukin 10 are found in severe
sepsis patients, and often is linked to mortality. Interleukin-10 high levels
have been found in human immunodeficiency virus-1 combination antiretroviral
therapy naïve patients, and the levels found to reduce when the patient is on
combination antiretroviral therapy [49] signifying there is increased
inflammation with human immunodeficiency virus-1 progression. Interleukin-10
has also, seen to promote the action and survival of Foxp3 regulatory T cells
[50].
Together with transforming growth factor beta,
Interleukin -10 as an inhibitory cytokine, reignforces regulatory T cell
suppressive function, maintaining a state of immune homeostasis. The positive
correlation in interleukin 10 and human immunodeficiency virus-1 viremia and
has been found to be a useful marker of human immunodeficiency virus-1 disease
progression. Some studies found high levels of interleukin 10 in plasma at
combination antiretroviral therapy initiation, compared to levels six months
later. While combination antiretroviral therapy naïve human immunodeficiency
virus-1 patients exhibit increased levels of interleukin 10, and its production
in human immunodeficiency virus-1 infection is associated with human
immunodeficiency virus-1 progression to AIDS ,
it has been postulated that combination antiretroviral therapy introduction
reduces the inflammatory response to human immunodeficiency virus-1 and this
lowers the levels of interleukin 10 in human immunodeficiency virus-1 patients.
Interleukin-10 both limits antigen presentation and modulates the local
cytokine micro-environment, preventing robust T cell responses. It has been
suggested that, CD4+CD25+FoxP3+ T regs which produce interleukin 10 maintain a
balance between immunosuppression and overactive responses and can be infected
by human immunodeficiency virus-1 virus, and that, in human immunodeficiency
virus-1 infection T regs regulate the immune system through T cell suppression
of inflammation and spread of virus [51,52]. It is postulated that all subsets
of T cells can produce interleukin -10, and at the peak of an inflammatory
response, the main source of interleukin 10 is antiviral CD4+ T cells and CD8+
T cells. Additionally, interleukin-10
limits the release of reactive oxygen intermediates from cells of immunity,
induction of nitric oxide synthase, and the production of nitric oxide.
Studies have shown that blocking of interleukin 10
enhances Th1 memory development and function, promotes Th1 priming, and
increases germinal center Th1 cells. While CD8+ T cells kill infected cells by
recognizing virus presented on MHC I molecules via antigen presenting cells,
Th1 cells allow the CD8+ T cells differentiation into effector cytotoxic
lymphocytes, and this activity is modulated by interleukin-10, which act as a
regulatory effector. The suppression of immune activation on the other hand
promotes latent viral reservoir formation and limits viral clearance.
Interleukin-10 produced in antiviral immunity by APCs and NK cells is a
counterbalance to proinflammatory state which protects tissue damage.
Additionally, the evasion of the immune response, and host regulated
immunosuppression can impair viral clearance, moreover, in T cell exhaustion,
effector functions of CD4+ T cells and CD8+ T cells are lost. As earlier
suggested, interleukin 10 targets many cells, and it’s produced by different
types of cells, leading to a wide anti-inflammatory activity. In the control of
viral infections, natural killer cells and natural killer T cells are pivotal
arm of innate immunity through the production of interleukin-10, additionally,
Macrophage activity has been seen as the main target of the interleukin-10
inhibitory effects. Interleukin-10 promotes cytokine production, NK cell
proliferation, and cytotoxicity.
Studies have suggested that cytotoxic CD8+ T
lymphocytes (CTL) are used to eliminate viruses, and other intracellular
pathogens. The suppressive effect of interleukin 10 targets specific genes such
as lipopolysaccharides, and inhibition of transcription. Similarly, recognition
of danger associated molecular patterns (DAMPs) and pathogen associated
molecular patterns (PAMPs) drives the antiviral state in antigen-presenting
cells (APC) which initiate innate immune response, and nterleukin-10 is induced
in macrophages, dendritic cells, natural killer cells, monocytes, neutrophils
and T cells. Interleukin-10 inhibits T cell responses via antigen presenting
cells (APCs) and can also limit T cell responses by acting through induction of
no responsiveness or anergic state directly on CD4 T cells. It is worthwhile
noting that, viruses trigger pattern recognition receptors (PRR) engagement
during early phase of infections after danger-associated molecular patterns
(DAMPs) or pathogen associated molecular patterns (PAMPs) recognition, followed
by a milliard of cytokines including interleukin 10.
Interleukin- 10 has been shown to act as a brake on
inflammation, however, effects on antiviral immune response depends on site of infection,
the virus, and immune response timing. As seen earlier, levels of
interleukin-10 have been found to correlate viral loads in human
immunodeficiency virus-1 patients. Some studies have postulated that, high
interleukin-10 levels may be protective in early human immunodeficiency virus-1
responses, and in acute infection, the cytokine may become detrimental as virus
persistence is promoted. Also the signalling of interleukin 10 also inhibits
Th1 cytokines production, and stimulates Th2 cytokines production, thus, the
anti-inflammatory response caused by interleukin 10 impacts negatively on
effector T cell, favouring persistence of human immunodeficiency virus-1
infection. In an immune response at peak level, interleukin 10 could enhance
CD8 T cells activity, and limit antigen presenting cell inflammation, and it is
at this phase that interleukin 10 is produced by CD4+ CD25+ Treg cells.
Human immunodeficiency virus-1(HIV- 1), being a
persistent viral infection has a high rate of morbidity and mortality and also
lacks efficient therapy, not to mention a functional cure. Interleukin-10 has
been shown to be induced in human immunodeficiency virus-1 infection, and is an
immunosuppressive cytokine that dampens proinflammatory responses, after virus
encounter. Since in the course of chronic human immunodeficiency virus-1
infection antiviral cytokines are not produced in plenty by CD4+ T cells and
CD8+ T cells, leading to persistent infections, T cell gene expression changes
such as elevated interleukin 10 production, transforming growth factor beta and
inhibitory receptor induction occur. As mentioned earlier, innate and adaptive
immune cells that produce interleukin 10 include dendritic cells, B cells, and
macrophages, which, after they secrete the cytokine, the produced interleukin
10 binds interleukin 10 receptor on the immune cells to trigger T cell anergic
state and to reduce antigen presentation. It is worthwhile noting that,
interleukin 10 can alter antiviral T cell function, through its effects on
antigen presenting cells, as the proliferation of antiviral Th1 cells and
cytokine production is limited by interleukin 10. While the control of
inflammatory responses from viral infections requires interleukin 10 regulatory
mechanisms, reservoir establishment and human immunodeficiency virus-1
persistence is aggravated by the secretion of interleukin-10.
Transforming growth
factor-beta (TGF-?),
Transforming growth factor -beta (TGF-?) is an
anti-inflammatory cytokine produced by T cells and B cells, and works by
inhibiting haematopoiesis, T cell and B cell proliferation, as well as
promotion of wound healing. Transforming growth factor-beta (TGF-?), a
pleiotropic cytokine with potent immune regulatory properties in the immune
system is produced by T regulatory cells,
whose numbers are reported to be increased in lymphoid tissues and
mucosa of human immunodeficiency virus-1 combination antiretroviral therapy
naïve patients, and are associated with disease progression [53]. In normal
development and homeostasis transforming growth factor beta plays an important
role [54]. Chronic inflammatory response in human immunodeficiency virus-1
patients on combination antiretroviral therapy is partially counteracted by
anti-inflammatory processes, which ironically exacerbates immunosuppression and
also causes development of non-communicable non-AIDS related disorders. It has
been reported that, transforming growth factor beta downregulates the release
of perforins and granzymes, synthesis of interferon gamma and Fas ligand
expression, and collectively this contributes to CD8+ T cells
cytotoxicity. TGF beta downstream
signalling and dysregulation leads too many diseases. Transforming growth factor-beta
(TGF-?) level has been found to be elevated in HIV-1 non adherent patients and
not in combination antiretroviral therapy adherent, and healthy controls [55].
Suggestions available so far include the blockage of transforming growth factor
beta, which would serve as human immunodeficiency virus-1 functional cure, when
applied to viral latency reduction [56]. During a normal inflammatory response,
transforming growth factor beta signalling plays a key role.
Higher levels of transforming growth factor beta have
been found in human immunodeficiency virus-1 patients in acute, sub-acute and
chronic infection when compared to the negative controls [57]. Transforming
growth factor beta has been shown to inhibit proliferation of resting memory
CD4+ T cells by inhibition of cell cycle and limitation of induction of
apoptosis. The suppressive functions of T regulatory cells is through
production of transforming growth factor beta, which inhibits T-helper (Th)1 and Th2 cell
differentiation and proliferation
achieved through inhibition of production of the transcription factors,
GATA-3 and T bet. Transforming growth factor beta is encoded by 33 genes in
mammalian cells, as a secreted, heterodimeric, and homodimer proteins which
controls the differentiation of cells [58]. While transforming growth factor-beta,
secreted by natural killer cells has
been shown to have a negative regulatory role in HIV infection, increased
transforming growth factor beta has been reported in human immunodeficiency
virus-1 combination antiretroviral therapy naive patients as reported, in
innate immune system, Transforming growth factor beta inhibits natural killer
(NK) cell interferon gamma production and
CD16 activation induced antibody-dependent cellular cytotoxicity (ADCC)
induced.
Transforming growth factor -Beta (TGF??) is an
anti-inflammatory immune regulatory inhibitor of excess inflammatory response
resulting from pro?inflammatory cytokines activity. In limiting immune activation, TGF beta reduces
the availability of activated CD4+ T cells, thus supporting human
immunodeficiency virus-1 replication and spread V. This cytokine has been shown
to remain persistently elevated in human immunodeficiency virus-1 combination
antiretroviral therapy and combination antiretroviral therapy naïve patients,
to counteract immune destruction by cytotoxic CD8+ T cells and the cytopathic
effects of human immunodeficiency virus-1, contributing to CD4+ T cells
depletion, resulting in immunosuppression and subsequent development of AIDS.
Transforming growth factor beta deregulation has been shown to lead to
anomalies and disease in the development process. Transforming growth
factor-beta (TGF-?) levels have been shown to be high in human immunodeficiency
virus-1 patients before commencement of combination antiretroviral therapy, and
remain high 12 months into treatment.
Transforming growth factor beta has been listed among major cytokines
that cause of immunosuppression in human immunodeficiency virus-1 infection, by
targeting both innate and adaptive immune systems and profibrotic activity as
well as suppressing the effects on CD4+T cells, in addition to regulation
of the proliferative and effector
functions of CD8+ T cells. Transforming growth factor beta characterizes human
immunodeficiency virus-1 disease severity. Antiretroviral therapy (ART) should
be given to all HIV-1 patients as soon as viremia is detected [59]. Similar
findings in a different study found decreased transforming growth factor beta
in patients with non-progressive human immunodeficiency virus-1 infection, and
increased levels were observed in patients with progressive human
immunodeficiency virus-1 infection.
The signalling of transforming growth factor beta has
been shown to promote human immunodeficiency virus-1 infection in both resting
memory and activated CD4+ T cells. Other studies have implicated Transforming
growth factor beta in regulation of humoral immune responses through
suppression of proliferation, survival, and differentiation of B cells into antibody secreting B cells and
the mechanisms are thought to be responsible for the suppressive effects of
transforming growth factor beta in IL-2, IL-4, and interferon gamma cytokine
production. The blockade of transforming growth factor beta has been suggested
to promote establishment of latency reservoir early in human immunodeficiency
virus-1 infection. To note, high levels of transforming growth factor beta are
produced in human immunodeficiency virus-1 infection in combination antiretroviral
therapy naïve and combination antiretroviral therapy experienced patients and
leads to immunosuppression contributing to progression of acquired
immunodeficiency syndrome in combination antiretroviral therapy naïve patients.
The majority of patients can start with the now 2-drug regime, or 3-drug regime
which include integrase strand transfer inhibitor. Currently, a long term
acting (4 weeks or 8 weeks), based on availability and regulatory body approval
may be adopted. For neutrophils some studies have reported that migration as
well as degranulation is inhibited by transforming growth factor beta while
others have reported the cytokine as having potent chemotactic and activating
factors for neutrophils. Transforming growth factor beta has also been shown to
inhibit activation and maturation of dendritic cells as well as inducing
dendritic cell apoptosis, impeding expression of costimulatory molecules
(CD40,CD80, CD86),antigen presenting capacity,
HLA class II molecules, production of tumour necrosis factor-alpha,
Interferon alpha, IL-12, and migration.
Additionally, TGF beta may have the potential of directly enhancing virus
replication by blocking adaptive human immunodeficiency virus-1 control
responses, which include virus specific CD8+ T cells responses as well as
humoral immunity (Dickinson et al., 2020). Early in inflammation, transforming
growth factor beta upregulates T regulatory cell production and promotes Th17
differentiation and later in inflammation, this cytokine may inhibit proliferation
of T regulatory cells thereby inhibiting immune responses, and thus
Th17/CD4+CD25+FoxP3+ T regs balance is important in maintenance of a normal
immune function (Theron et al., 2017a).
Human immunodeficiency virus-1 patients continue to
experience low-grade, persistent systemic inflammation, even on attaining viral
suppression after combination antiretroviral therapy introduction. Human
immunodeficiency virus-1 patients with nonprogressive infection have been
reported to have lower TGF beta levels as compared to the progressors.
Transforming growth factor beta also increases CD69 expression and decreases
CD25 expression on CD4+ T cells, showing it can modulate differentiated CD4+ T
cells. The anti-inflammatory response that ensues exacerbates immunosuppression
and also predisposes the patient to non-AIDS-related, non-communicable
disorders. As reported, pplasma transforming growth factor beta is elevated in
human immunodeficiency virus-1 patients, as opposed to seronegative
individuals, which correlates with T cell levels, high, and disease progression
(Dickinson et al., 2020). Studies have shown that transforming growth factor
beta which is an anti-inflammatory cytokine remains elevated in both virally
suppressed and unsuppressed patients, which may be confounded by residual virus
in the suppressed patients, and T regs are protected from apoptosis and
promotion of induced Tregs differentiation during thymic development by
transforming growth factor beta. Some studies have attributed secondary
immunosuppression to having been caused by over production of transforming
growth factor beta (TGF-?), as a cause of immunosuppression in human
immunodeficiency virus-1 infection.
Transforming growth
factor beta one adaptive immune system
Transforming growth factor-beta (TGF-?) has been shown
to inhibit Th1 and Th2 cell proliferation and differentiation through
inhibition transcription factors, T bet, and GATA-3 production. BLIMP-1, which
is a transcriptional repressor is upregulated by transforming growth factor
beta 1, thereby promoting human immunodeficiency virus-1 latency and reservoir
formation [60]. Transforming growth factor-beta (TGF-?) also negatively affects
the proinflammatory functions of macrophages such as inhibition of MyD88-dependent
Toll-like receptor signalling, expression of inducible nitric oxide synthase,
and matrix metalloproteinase, and has been shown to be induced by human
immunodeficiency virus-1 trans activator of transcription (Tat), which could be
behind the immunosuppressive effects of Tat. Some study has also reported this
cytokine to be systemically induced early in human immunodeficiency virus-1
infection, and been demonstrated to remain upregulated throughout infection.
Throughout it’s working mechanism, transforming growth factor beta suppresses
the production cytokines such as interleukin (IL)-2, and interferon (IFN)-?,
and ?2 subunit of the IL-12 receptor (IL-12R) on CD4+ T cells loss, leading to
IL-12 unresponsiveness. Additionally, transforming growth factor beta also
inhibits immune responses through CD4+, CD25+, Foxp3+ Tregs regulation, and so
suppressing T cell functions.
Effects of TGF-? on
cells of the innate immune system
Transforming growth factor beta inhibits NK cell
interferon gamma production and also CD16 activation induced ADCC. Macrophages
proinflammatory activities such as inhibition of matrix metalloproiteinase-12
and expression of inducible nitric oxide synthase are negatively affected by
transforming growth factor beta. Similarly, transforming growth factor beta
downregulates of MyD88-depended Toll-like receptor signalling pathway. Rapid
secretion of numerous cytokines following human immunodeficiency virus-1
infection is a characteristic of the innate immune system, and the cytokines
play a crucial role in control of the virus, as well as disease pathogenesis.
Additionally, TGF beta maintains a resting state in immune cells through
blocking of cell activation and proliferation [61]. After viremic spread, TGF
beta, which is a pleiotropic cytokine is induced rapidly, and remains
upregulated throughout infection. Establishment of human immunodeficiency
virus-1 latency reservoirs may be exacerbated by transforming growth factor
beta upregulation through the increasing of resting memory CD4+ T cells, and
also homing lymphoid organ of central memory CD4+ T cells that are infected.
TGF beta plays an important role during human
immunodeficiency virus-1 infection, in regulation of CD8+ T cells, and as
reported, blocking the activities of TGF beta may decrease immune activation,
and limit pathogen clearance. It has been reported that, human immunodeficiency
virus-1 is promoted by transforming growth factor beta in resting and activated
memory T cells, and that even after many years of combination antiretroviral
therapy, high levels of transforming growth factor beta have been reported.
Transforming growth factor beta has been shown to upregulate the expression and
frequency of CCR5 human immunodeficiency virus-1 coreceptor and so in
CCR5-tropic virus, augmenting viral infection of activated and resting CD4+ T
cells. The pleiotropic effects of interferon gamma is on proliferation,
activation, and differentiation of many immune cells, and upon human
immunodeficiency virus-1 infection, reactivation has been shown to increase in
the presence of transforming growth factor beta. While human immunodeficiency
virus-1 latency in memory CD4+ T cells is supported by transforming growth
factor beta Sydney [62], reactivation of human immunodeficiency virus-1
reservoirs and immune responses has been suggested to occur through blockade of
transforming growth factor beta, and enhances anti- human immunodeficiency
virus-1 immune responses. As viremia escalates, human immunodeficiency virus-1
infection leads to a cytokine storm, with an elevated miliad of cytokines and
chemokines as a result of acute human immunodeficiency virus-1 viral
replication. Human immunodeficiency virus-1 persists latently as reservoirs in
CD4+ T cells during combination antiretroviral therapy (cART).
Viral burden and human immunodeficiency virus-1 latency has been shown to be increased by transforming growth factor beta, as high levels have been observed in human immunodeficiency virus-1 combination antiretroviral therapy naïve patients, and the high levels have been found in lymphoid tissues, cerebrospinal fluid and in the blood of human immunodeficiency virus-1 patients. Direct cytopathic effects of human immunodeficiency virus-1 and destruction by cytotoxic CD8+ T cells contribute majorly to depletion of CD4+T cells leading to progressive immunosuppression which culminates in AIDs development. Transforming growth factor-beta (TGF-?), alongside interleukin 10 in human immunodeficiency virus-1 infection, have been postulated to play negative roles, working against the pro-inflammatory cytokine activities. Increased levels of transforming growth factor beta have been associated with proliferation of defective T cells and B cells, and in human immunodeficiency virus-1 infection, additionally, the production of transforming growth factor beta has also been shown to be contributed by human immunodeficiency virus-1 proteins.
Effects of
TGF-?1 on host, promoting HIV-1 reservoir load
Human immunodeficiency virus-1 receptor CCR5 are
increased leading to a high number of integrated HIV DNA, and the resultant is
suppression of miR-9-5p by transforming growth factor beta 1 leading to
upregulation of transcriptional repressor BLIMP-1, causing latency and increased
viral load. Transforming growth factor beta-1 also inhibits immune responses
indirectly via regulation of CD4+, CD25+, Foxp3+ Tregs which play the role of
suppression of T cell functions activities which are regulated indirectly by
transforming growth factor beta in the process of inhibiting immunresponses.
Interleukin
17/Interleukin 10 ratio in human immunodeficiency virus-1 infection
Human immunodeficiency virus-1 (HIV-1) control by the
host innate immune system is essential, nonetheless, the excessive antiviral
activity should be carefully regulated to prevent high inflammation and
accompanying tissue damage at any phase of the infection. Interleukin-17 and
interleukin-10 cytokines have been found to be related to TH 17, and T regs
respectively, as they are expressly produced by the cells [63]. Interleukin-17
from Th17 cells stimulates chemotaxis of neutrophils, dampens cytotoxic T cell
activity, and induces a Th2 skewed immune response, while T regulatory cells
inhibit excessive immune responses and promotion of early recruitment of
virus-specific CD8+ T cells. Interleukin-10, from CD4+CD25+FoxP3+ T regs and
interleukin 17 from Th17 T cells balance is a state of equilibrium that allows
quick protective immune responses against infectious agents while curtailing
the potential for causing harm to the host. A balance of Th17/Treg ratio is
pivotal in fine tuning the inflammatory response to viral infections and if
this balance is properly maintained, the pathologic effects of interleukin 17
may be held in check, and beneficial functions will outweigh the pathogenic
effects. Studies have shown some imbalance in interleukin 17/ interleukin 10 in
human immunodeficiency virus-1 patients and this imbalance has been suggested
to be the main promoter of human immunodeficiency virus-1 replication. Some
studies have suggested that lower levels of interleukin 17 are associated with
high interleukin 10 release. As earlier suggested, it has been shown that, Th17
and CD4+CD25+FoxP3+ T regs in inflammatory outcomes and development have
opposite roles. Other studies have postulated that in human immunodeficiency
virus-1 infection, interleukin 17 plays both a pathogenic and protective roles.
It is plausible that balancing of mucosal Th17/ CD4+CD25+FoxP3+ T regs ratio at
combination antiretroviral therapy initiation leads to a good virologic
response to combination antiretroviral therapy and maintenance of higher CD4+ T
cell counts [64]. Additionally, it has been found that, early in inflammation,
Th17 provides a link between adaptive and innate immunity and maintains mucosal
barrier integrity while CD4+CD25+FoxP3+ T regs inhibits activities of T
lymphocytes to reduce excess autoimmune symptoms, thus reducing body resistance
to pathogens thereby preventing inflammation [65]. To note, Th17, being very
permissive to human immunodeficiency virus-1 infection may promote the
intracellular replication of virus, and thus, presence of these cells
correlates with human immunodeficiency virus-1 pathology. Thus, the induction
of expression of inflammatory factors such as CXC chemokines, and G-CSF is done
by interleukin 17, in addition to participation in immune responses against
viruses. Conclusively, it is worth noting that the excess activity of
interleukin 17 when not counteracted by interleukin 10, can lead to a
proinflammatory effect, leading to autoimmunity and tissue damage.
Viral load
in combination antiretroviral therapy
Highly active antiretroviral therapy (HAART) currently
referred to as combination antiretroviral therapy (cART) reduces mobility and
mortality in the majority of human immunodeficiency virus-1 infected
individuals and is used as a life time therapy because as at this period,
treatment does not clear the human immunodeficiency virus-1 reservoir. Combined
antiretroviral therapy improves the quality of life for human immunodeficiency
virus-1 patients, as more strides are being made towards improving the clinical
management and outcomes for at risk populations. First line combination
antiretroviral therapy involves a combination of three to four ARVs, including
integrase inhibitors (INIs), Nucleoside reverse transcriptase inhibitors
(NRTIs), Protease inhibitor (PIs), Nonnucleoside reverse transcriptase
inhibitors (NNRTIs), and fusion inhibitor (FIs) [66]. ART should be given to
all human immunodeficiency virus-1 patients as soon as viremia is detected. It
has been postulated that, systemic inflammation is decreased by combination
antiretroviral therapy, but rarely achieved to levels are comparable to human
immunodeficiency virus-1 non infected individuals. Viral load and CD4+ T cell
count are currently being utilized in prediction of human immunodeficiency
virus-1 disease outcome [67], but the levels may not give early prediction of
drug resistance in human immunodeficiency virus-1 patients. It has been
postulated that, detectable viral load after close to 6 months of combination
antiretroviral therapy could be related to the progression of human
immunodeficiency virus-1 infection and it has been reported that there is a
shift from Th1 to Th2 cytokine profile which has been associated with human
immunodeficiency virus-1 disease progression [68].
The majority of patients can start with the now 2-drg
regime, or 3-drug regime which include integrase strand transfer inhibitor.
Currently, a long term acting (4 weeks or 8 weeks), based on availability and
regulatory body approval. In cases where combination antiretroviral therapy is
interrupted, viral rebound occurs. Clonal expansion takes place in human
immunodeficiency virus-1 infected cells, and the clonally expanded cells
increase with time. It has been postulated that, more than 50% of the clonally
expanded cells are maintained through latent reservoirs. Viral rebound is
contributed to by the human immunodeficiency virus-1 infected clonally
expanding cells. In human immunodeficiency virus-1 patients on combination
antiretroviral therapy, the viral load decrease is accompanied with an increase
in CD4+ T cells and CD8+ T cells [69]. Combination antiretroviral therapy has
been known to reduce human immunodeficiency virus-1 viral load to undetectable
levels, and halts human immunodeficiency virus-1 replication. Clonal expansion
of in human immunodeficiency virus-1 infected cells is driven by among others,
homeostatic proliferation, antigen driven proliferation, and human
immunodeficiency virus-1 site-dependent integration proliferation. The
persistence of human immunodeficiency virus-1 human immunodeficiency virus-1 in
latent reservoir is a great barrier to cure. Therapy safety and effectiveness
monitoring before and during administration is key. Higher levels of low level
viremia was associated with virologic failure. Studies have shown that,
episodes of high human immunodeficiency virus-1 viral load are preceded by
persistent viremia and a possibility of resistance development.
Laboratory tests
which may include genotyping, human immunodeficiency virus-1 RNA level, and CD4
cell count are recommended, at specified points for co-infections and for the
general population infected by human immunodeficiency virus-1 before and during
therapy [70]. Presumably, on combination antiretroviral therapy initiation,
viral suppression should be attained within 24 weeks, and in clinical
management, within 6 months of combination antiretroviral therapy initiation,
additionally, in the event of first line combination antiretroviral therapy
failure, second line is initiated, and is comprised of NRTIs and
ritonavir-boosted protease inhibitor. Virologic failure is noted to be rare,
though switching therapy may be done for convenience, among other reasons. To
note, virologic suppression has been shown to be achieved in more than 90% of
first line combination antiretroviral therapy patients since at least one drug
targets a step of human immunodeficiency virus-1 replication, thus, most immune
biomarkers are reported to be normalized in human immunodeficiency virus-1
combination antiretroviral therapy suppressed patients, and move towards human
immunodeficiency virus-1 negative levels. In
human immunodeficiency virus-1 patients on combination antiretroviral
therapy, immune dysregulation is shown to be
minimized due to human immunodeficiency virus-1 suppression and immune
recovery, is exhibited by an increase in CD4+T cell count, following successful
combination antiretroviral therapy, additionally, cytokines are also
normalized, improving the stability of the system, as the goal of combination
antiretroviral therapy is to reduce human immunodeficiency virus-1 related
mobility and mortality through inhibiting of human immunodeficiency virus-1
replication. It has been suggested that combination antiretroviral therapy
failure in human immunodeficiency virus-1 patients can be identified in three
ways; immunologically, virologically, or clinically [71].
Some studies have defined virologic failure by a
persistently detectable viral load of over 1000copies/ml within a three months
interval after starting combination antiretroviral therapy [72]. Dolutegravir (DTG)-based
therapies has been recommended as the preferred first-line antiretroviral
therapy option [73]. Persistent low level viremia has been associated with
virologic failure, AIDS, genotype resistance, and adherence difficulties. While
some studies have established Resistance -associated mutations to be found in
the gag and Tat genes of human immunodeficiency virus-1 [74], other studies
have delinked viral resistance or less drug concentration to persistent low
level viremia [75]. There is a recommendation to lower human immunodeficiency
virus-1 virologic failure threshold from 1000copies/ml to 50 copies/ml. For a
regimen switch, tolerability, drug resistance history, treatment history and
drug adherence should be considered. Reasons for virologic failure include:
patient adherence -related factors such as high pill burden and missed clinic
appointments, and regimen related factors such as reduced efficacy and
sub-optimal pharmacokinetics. Combination antiretroviral therapy initiation in
human immunodeficiency virus-1 patients reduces T cell activation, as there is
immune reconstitution [76].
Once the CD4+ T cell count hits below 200 cells/ml,
there is a recommendation against routine monitoring in patients who are
clinically well. Viral suppression remains below the UNAIDS target of 90%
achievable by 2020 in human immunodeficiency virus-1 patients on combination
antiretroviral therapy. (“Incidences and Factors Associated with Viral
Suppression or Rebound among HIV Patients on Co [77]. The Kenya 2018 combination
antiretroviral therapy guidelines define persistent low level viremia as having
detectable viral load, of less than 1000copies/ml on two or more consecutive
tests done after previous human immunodeficiency virus-1 suppression. The goals
of antiretroviral therapy have been known to be prevent onward transmission of
human immunodeficiency virus-1 infections, Prolong the life expectancy and
improve quality of life, reduce human immunodeficiency virus-1 non-infectious
and infectious morbidities, provide durable and maximum suppression of viral
load, and reduce the adverse effects of treatment. Persistent immune activation
is characteristic of viral replication, increased pro-inflammatory cytokines,
and loss of the gut mucosa’s integrity, and can predict the occurrence of
depletion of CD4+ T cells. Notably, the viral load has been shown to be
maintained by combination antiretroviral therapy to levels below detection
limit for the majority of treated patients. High viral rebound rate (41% of the
study population) was found in human immunodeficiency virus-1 patients on
combination antiretroviral therapy. Well-tolerated, and sustainable treatment,
alongside good and enhanced adherence is all necessary in order to achieve
suppression of human immunodeficiency virus-1 replication in human
immunodeficiency virus-1 on combination antiretroviral therapy.
HIV viral
load testing
Effective combination antiretroviral therapy leads to
viral load reduction to below 50 copies/mL in human immunodeficiency virus-1
patients, however events of persistent low level viremia, with varying
virological consequences are still eminent. Restoration of pathogen specific
immune function improves with an increase in CD4+ T cell count, and this is the
result of prolonged human immunodeficiency virus-1 suppression, which in
addition, reduces human immunodeficiency virus-1 related mortality and
morbidity. A study reported some of the factors associated with viral
suppression to include widow status, good adherence, and world health organization
stage I, while the factors associated with viral rebound included WHO stage II,
36 months duration on ART, and poor adherence to antiretroviral therapy. Risk
factors for low level viremia include higher baseline viral load measurements,
non-adherence to medication, low CD4 cell count at base line, and
Non-nucleotide reverse transcriptase inhibitors (NNRTI) use, among others,
therefore intensifying and modifying combination antiretroviral therapy has the
potential, and leads to a decrease in virologic failure. It has been suggested
that, when human immunodeficiency virus-1 is poorly controlled, this leads to
the risk of emergence of drug resistance, transmission of human
immunodeficiency virus-1 infection, and death [78]. Clonal expansion and viral
reservoir size have been postulated as the possible causes of persistent low
level viremia. Additionally, it has been observed that patients with low level
viremia have high chances of virologic failure. It has been shown that,
patients who adhere to treatment resume a near to normal life style, although
adherence has been reported as key challenge and focus in human
immunodeficiency virus-1 patients on antiretroviral therapy. While some studies
have reported good progress in attaining of undetectable viral load for more
than 2 years, which points to the achievement of the united nation’s 2030
objective of human immunodeficiency virus-1 control, there seems to be more
incidences of viral rebound in human immunodeficiency virus-1 patients on
combination antiretroviral therapy.
While persistent low level viremia has been associated
with virologic failure, alteration of immune status, and emergence of drug
resistance, there has been no reported association between occurrence of blips
and immunologic and virologic failure. Some of the known causes of unsuppressed
human immunodeficiency virus-1 during combination antiretroviral therapy most
often are taking inappropriate combination antiretroviral therapy, infection
with drug-resistant strains, and combination antiretroviral therapy
non-compliance. Viral suppression was listed as part of the UNAIDS 2014
sustainable development goals. While studies have found and reported that
persistent low level viremia can lead to viral shedding, and human
immunodeficiency virus-1 reservoir expansion, combination antiretroviral
therapy is meant to maintain undetectable viral load, avoid emergence of drug
resistance, and decrease human immunodeficiency virus-1 transmission, thereby
keeping low level viremia at bay, [79]. Without a serious and extremely
compelling reason, antiretroviral therapy should not be stopped, instead, in
cases of reported drug toxicity, attempts to switch regime should be exploited.
Recent reports from the world health organization (WHO) guidelines has placed treatment
failure at confirmed viral load of greater than 1000 copies/ml, while the US
has placed virologic failure at 200copies/ml viral load. Based on this, and
considering the current records, world-wide, 35% of human immunodeficiency
virus-1 patients had achieved viral suppression, as reported by UNAIDS, 2019
report. The viral load should be sufficiently suppressed, should attempts to
switch a regime due to toxicity ensue, to avoid the development of drug
resistance to the new drug. Available diagnostics enable detection and
identification of virologic suppression with effective treatment, to be below
undetectable levels, based on many standard assays sensitivity. Thus, human
immunodeficiency virus-1 treatment success is defined by viral load below
detection level, when done by conventional testing algorithms. To achieve the
UNs 90-90-90 target by 2020 as forecasted, would be important towards AIDS
pandemic elimination by 2030. (“Incidences and Factors Associated with Viral
Suppression or Rebound among HIV Patients on Combination Antiretroviral Therapy
from Three Counties in Kenya,” 202. Recent studies have further reported that
combination antiretroviral therapy does not eradicate residual viremia, as has
been evidenced by many patients after years of treatment, since viral
persistence is still reported in many instances.
Virologic suppression has been defined as a confirmed
viral load below detection level, while virologic failure is defined as the
inability to achieve or maintain a viral load of less than 200copies /ml by or
after one year of starting combination antiretroviral therapy. The objective of
providing antiretroviral therapy should always be to provide a virologic
suppression achievable regime. Since low-level viremia has been shown to be a
predictor of virologic failure in human immunodeficiency virus-1 patients on
combination antiretroviral therapy, it has been postulated that human
immunodeficiency virus-1 being one of the ten causes of mortality in adults, is
uncontrolled in low level viremia, and exacerbates the pandemic on rebound.
Currently, WHO does not have guidelines on change of clinical care for human
immunodeficiency virus-1 viral load of less than 1000copies/ml, and this allows
occurrence of low level viremia in human immunodeficiency virus-1 patients on
combination antiretroviral therapy. Achieving these targets depends squarely on
trend monitoring of viral suppression and viral rebounds, and by understanding
the factors revolving around viral rebound, in order to effect interventions.
Viral load testing has been shown to be key in human immunodeficiency virus-1
monitoring. Statistics have shown that, approximately at least one out of five
patients undergoing combination antiretroviral therapy have experienced
episodes of detectable viremia in form of blips, while 4-10% of patients on
combination antiretroviral therapy have shown persistent low level viremia. Low
level viremia has been found as a grey zone between undetectable viral load,
and virologic failure. Virologic failure has been defined as a confirmed viral
load of more than 50 copies /ml on viral load measurements taken 2-3 months
apart consecutively, while under intensive and optimal adherence counselling.
Human immunodeficiency virus-1 viral load of less than
100copies/ml in patients on combination antiretroviral therapy has been
seemingly thought of as insufficient, however it is the persistence of low
level viremia in this occurrence that has harmful effects. Some studies found,
at next viral load testing, patients with viral load of less than 200copies/ml
had high odds of viral non-suppression, and low level viremia at the next viral
load. Other studies have indicated that patients with persistent low level
viremia without regimen change will progress to virologic failure. Previous
studies and guidelines had indicated treatment failure to be a viral load of
1000 copies/ml, but robust evidence now suggests, a viral load of more than 50
copies/ml can result to virologic failure. The European AIDS Clinical Society
defines virologic failure as a viral load greater than 50copies/ml, and
recommends a change of therapy, which is more stringent than WHO, that requires
a change in therapy when the viral load is greater than 1000copies/ml. In
Kenya, at the initiation of ART, viral load is recommended, and for effective
monitoring, this should be followed by a six-month interval viral load testing.
It is now revealed that human immunodeficiency virus-1 transmission can occur
even with a viral load of 200copies/ml of blood. In a study conducted by, the
findings indicated a low level viremia in 16% of the study population, and
11.4% patients had virologic non-suppression. Similarly, from the adjusted
risk, it was found that patients at increased risk of virologic failure were
those with low level viremia. Additionally, in Africa however, WHO guidelines
has set the virologic failure threshold at a viral load of more than
1000copies/ml, and a combination antiretroviral therapy switch to be done at
this point [80]. To note, monitoring of
viral load recommendation is at six months, and 12 months upon combination
antiretroviral therapy initiation, and thereafter, monitoring should be done
annually. Studies have shown, viral replication even at these low levels, when
it is sustained, is capable of leading to virologic failure, as well as
accumulation of drug resistance mutations. Based on UNAIDS report 2019, the
achievement by Kenya of the 90-90-90 so far is 89% for the first “90”, 77% for
the second “90”, and no data for the third “90”. (UNAIDS 2019).
A lot of inflammation has been observed in low level
viremia and various agencies have defined low level viremia differently; for
instance, the European Acquired Immune Deficiency Syndrome (AIDS) Clinical
Society (EACS) defines low level viremia as a viral load between 20 to 50
copies/ml, the Department of Health and Human Services guidelines (the USA,
2016), defines low level viremia as viral load between 50 to 200copies, while
WHO guidelines have defined low level viremia as viral load between 50 to 999copies/ml.
Some of the factors associated with persistent low level viremia have been
shown to include genotypic resistance, vaccinations, concomitant infections,
intermediate viral loads (200-399) copies/ml, High viral loads (400-999)
copies/ml, baseline CD4 count, and combination antiretroviral therapy adherence
difficulties [81]. Some of the reasons attributable to high viral loads have
been reported as drug absorption difficulties or drug-drug interactions altered
pharmacokinetics leading to inadequate antiretroviral therapy drug levels,
transmitted and acquired prescribed antiretroviral therapy resistance, and most
commonly, patient adherence inadequacy. Patients who have virologic
non-suppression need a repeat viral load testing, as well as adherence
counselling, while patients with more than two tests consecutively indicating
virologic non-suppression need a review for combination antiretroviral therapy
review. The global human immunodeficiency virus-1 guidelines recommend
preferably viral load as the combination antiretroviral therapy monitoring
strategy, thus, the human immunodeficiency virus-1 programmes that base on WHO
guidelines, have considered patients with viral loads of less than
1000copies/ml to be virologically suppressed. In first line failing
antiretroviral therapy, it is recommended that there should be enhanced
adherence counselling, followed by a repeat viral load measurement in 2-3
months.
While viral load testing is an important tool used in
monitoring combination antiretroviral therapy response in human
immunodeficiency virus-1 patients, undetectable human immunodeficiency virus-1
viral loads as done by routine assays has often been considered as a marker for
successful combination antiretroviral therapy. As seen earlier, some studies
have found virologic non-suppression in human immunodeficiency virus-1
patients. Factors associated with virologic rebound have been found to include
nutrition, adherence problems, and rural residency [82]. A great concern to physicians is the
puzzle of patients presenting with low level viremia, despite self-reported
adherence, as some observational studies found an association between very low
level viremia with subsequent virologic rebound. For human immunodeficiency
virus-1 patients, virologic suppression is the hallmark of successful ART. In
resource limited settings, WHO recommends measurement of viral load as a
preferred strategy for combination antiretroviral therapy response in human
immunodeficiency virus-1 patients. It has however been postulated that
undetectable viral load varies by laboratory assay used, and varied technical
properties. The UNAIDS “90-90-90” proposed target by the year 2020 alludes that
90% viral suppression should have been achieved by patients on ART, 90% status
knowledge by all infected, and a further 90% human immunodeficiency virus-1
diagnosed patients should have been put on ART
[83]. Should the result of the viral load test come as less than 50
copies/ml, the recommendation is that, the patients may be introduced to DTG+
the same two NRTs the patient was on. If on the other hand the outcome of the
viral load result is more than 50copies /ml, then it is recommended, a switch to
a second line regime that includes two NRTs + DTG, considering regime
algorithms. Proper human immunodeficiency virus-1 suppression reduces virus
transmission, development of resistant mutations, and improves clinical
outcomes, and switching of combination antiretroviral therapy in human
immunodeficiency virus-1 patients to 100 copies/ml has led to more patients
with low level viremia attaining viral suppression.
As viral load testing is being embraced as the means
to verify virologic suppression, drug resistance testing is not routinely done
in the majority of human immunodeficiency virus-1 care centers possibly due to
the high cost, and technical requirement to undertake the testing [84]. As
reported earlier, human immunodeficiency virus-1 virologic failure has been
defined by a viral load of more than 1000copies/ml as defined by WHO
guidelines. In resource endowed settings, virologic failure is however defined
as two consecutive viral loads of less than 200copies/ml, and this should
trigger a switch of combination antiretroviral therapy. Drug resistant
mutations and adherence inconsistencies have been suggested as the major
barriers to sustained virologic suppression in human immunodeficiency virus-1
patients on combination antiretroviral therapy [85]. Practically, low level
viremia study is hindered by problems in carrying out human immunodeficiency
virus-1 genotyping, occasioned by less
plasma human immunodeficiency virus-1 -RNA required for successful genome amplifications.
Drug resistance mutations were reported in 15% of the sampled patients, who had
experienced bounds of virologic failure defined by a viral load of more than
1000copies/ml. As reported earlier, the efficacy in antiretroviral is done
through monitoring of the viral load and CD4 cell count, and key to note, the
endpoint for ART efficacy is reported as a sustained virologic suppression of
less than 50 copies /ml, and CD4+ T cell count monitoring can be stopped on
achieving a count of 400 cells/ml.
Since HIV-1 drug resistance testing helps in choosing
the right combination antiretroviral therapy, predicting virologic failure, and
preserving the regime in use, some studies have estimated a 0.4%-38.7% low
level viremia experience in human immunodeficiency virus-1 patients on
combination antiretroviral therapy. Using different virologic failure threshold
across agencies poses different definitions to low level viremia. Design
mechanisms to address adherence barriers such as food security, non-disclosure,
alcohol use and depression, as well as the misconceptions around antiretroviral
therapy. In order to monitor treatment efficacy, the world health organization
(WHO), in 2013 recommended the use of viral load testing. It has however been
noted that, very few concerned entities have implemented this at large scale. A
number of studies have observed an association between low level viremia and
drug resistance mutations in human immunodeficiency virus-1 patients on
combination antiretroviral therapy and suggested viral load testing as the best
monitoring tool to ascertain virologic suppression, though this may come in
handy too late when routine viral load testing is done at three to six month
follow-up time. The most desired outcome in human immunodeficiency virus-1
patient’s management is viral suppression, which in the current era, can
effectively be achieved by antiretroviral therapy. 37% of patients on ART were
found to have virologic failure. It is also hypothesized that subsequent
virologic failure and impairment of combination antiretroviral therapy options
are the result of low level viremia. Effective combination antiretroviral
therapy is paramount to eradication of human immunodeficiency virus-1, and WHO
has listed combination antiretroviral therapy as one of the 90-90-90 targets,
where the third 90 was to ensure 90% viral suppression in human
immunodeficiency virus-1 patients on combination antiretroviral therapy by the
year 2020.
A study found that, on initial routine viral load
test, virologic failure was found in patients whose virologic suppression was
low. Dire consequences may however be experienced by some patients on ART who
may revert to viral rebound. Studies have suggested that transmitted human
immunodeficiency virus-1 drug resistance among other clinical characteristics,
is associated with the time to viral suppression and virologic failure [86]
additionally, two viral loads in sequence, of greater than or equal to
1000copies/ml was considered by WHO 2016 as virologic failure [87-89]. As seen
before, recent studies have postulated that, in patients on first line
combination antiretroviral therapy, transmitted drug resistance may lead to
virological failure, as there has been reported immune activation in human
immunodeficiency virus-1 patients even with combination antiretroviral therapy.
It is suggested that, for human immunodeficiency virus-1 patients on
combination antiretroviral therapy with viral loads more than 200 copies/ml,
there is a requirement for frequent viral load testing to help in planning for
regime switch [90]. From the results of a CDC survey that was done in 2015, it
was reported that only two countries among seven sub-Saharan countries tested
the viral load of more than 85% of human immunodeficiency virus-1 patients on
ART, and four countries tested less than 25% human immunodeficiency virus-1
patients on ART. Sustained antiretroviral therapy which has increased the viral
suppression success and a reduction in the HIV-AIDs related deaths has been the
focus on the fight against human immunodeficiency virus-1.
It has been reported that by 2018, 53% of human
immunodeficiency virus-1 patients on combination antiretroviral therapy had
suppressed viral load while 47% had detectable viral loads at varied levels,
and that drug regimen has been considered as an independent factor associated
with virologic failure [91]. Human immunodeficiency virus-1 RNA levels
estimation is the standard way of determining human immunodeficiency virus-1
replication [92]. Routine viral load testing was introduced in Kenya in 2013. The use of human immunodeficiency virus-1 VL
monitoring for identification of combination antiretroviral therapy failure has
been recommended by WHO guidelines on treatment of human immunodeficiency
virus-1 [93]. As earlier reported, after periods of combination antiretroviral
therapy, viral load has still been detected in human immunodeficiency virus-1
patients. Combination antiretroviral therapy successes include good clinical
outcomes, however when first line combination antiretroviral therapy fails, the
benefits of combination antiretroviral therapy reduce, and virologic failure
may result. Virologic failure is when there is a human immunodeficiency virus-1
plasma VL of ? 1000 copies/ml after previously attaining a human
immunodeficiency virus-1 plasma VL of ? 1000 copies/ml [94,95]. It has been
found that, while routine viral load testing has been recommended by WHO for
human immunodeficiency virus-1 patients on ART, access to the
resource-intensive and expensive laboratory test remains suboptimal. Current
management guidelines for virologic failure is by adherence intervention after
first detected virologic failure , and a viral load test repeat three months
thereafter; a second line combination antiretroviral therapy is recommended if
the second VL confirms virologic failure [96,97]. In many cases, intermittent
levels of low-level viremia followed by a return to suppression without a
change in therapy-“blips” are experienced prior to virologic failure [98,99].
Among the patients on first line antiretroviral therapy, viral suppression has
been reported, based on epidemiological studies, and as such, if streamlined
care is utilized, there is the hope of human immunodeficiency virus-1
eradication. It has been reported that human immunodeficiency virus-1 Patients
on combination antiretroviral therapy and with viral blips are at risk of
virologic failure [100,101]. While drug resistant viruses are found in human
immunodeficiency virus-1 patients with prolonged viral load decline [102],
persistent viremia has been associated with high risk of virologic failure, and
development of drug resistant mutants.
Viral load measurement has been used for decades in
high resource settings and this is majorly what is being used to determine
response to combination antiretroviral therapy [103]. The dangers associated
with viral rebound include treatment failure, the potential for human
immunodeficiency virus-1 transmission, antiretroviral therapy resistance, and
an increased vulnerability to other illnesses. Most patients were found to have
viral loads greater than 1000copies /ml during three visits, of which, some
mutations were recorded, and out of the mutations, a number resulted into
virologic failure [104]. In Kenya viral
load testing is done at six months and twelve months after combination
antiretroviral therapy initiation, then annually thereafter, for patients with
undetectable VL. For patients with viral loads ? 1000copies/ml, a follow-up is
done as per guideline algorithms, in which the patient receives a human
immunodeficiency virus-1 viral load repeat test three months later. A second
viral load within this time frame surmounts to treatment failure [105]. Viremia
likely occurs in patients who took long to be initiated on combination
antiretroviral therapy, and also the presence of virus in reservoirs in
immunological niches such as lymph nodes. The presence of residual virus leads
to persistent immune activation, and this could lead to viremia, and further
culminate to virologic failure that comes with morbidity and mortality [106].
The increased risk of human immunodeficiency virus-1
mortality and morbidity also hampers the achievement of UNAIDS agenda 95-95-95
targets by 2030. As earlier reported, WHO 2016 guidelines have placed a human
immunodeficiency virus-1 viral load of ? 1000copies/ml threshold, that a repeat
viral load test within 6 weeks has to be done, together with enhanced
counselling, and human immunodeficiency virus-1 viral loads of greater than
1000 copies/ml require a switch to second line combination antiretroviral
therapy [107]. Based on research studies so far, viral suppression as a result
of viral rebound has not received much attention in Kenya, though reports
available indicate upscaled viral load uptake. Viral load compared to
immunologic and clinical indicators in human immunodeficiency virus-1 patients
on combination antiretroviral therapy helps in identifying non-adherent
patients and early detection of treatment failure. Virologic failure as defined
by WHO is a viral load threshold of 1000copies/ml, a point at which the risk of
emergence of drug resistance and subsequent virologic failure has been shown to
occur, and is reporter to be a function of persistent low-level viremia of
between 50-999copies/ml. More reports involving virologic rebound after periods
of suppression have been recorded. Further and more recent studies have
postulated that higher levels of viral load and persistent low level viremia in
human immunodeficiency virus-1 patients on combination antiretroviral therapy
increased the risk of virologic failure. Patients on combination antiretroviral
therapy have been shown to by some studies to reach HIV RNA of less than 50
copies /ml blood within 3-6 months after initiation of combination
antiretroviral therapy. Additionally, intermittent low-level viremias have been
reported in up to 50% of human immunodeficiency virus-1 patients on combination
antiretroviral therapy. More factors associated with virological failure
include the patient being at WHO stage 3 and 4 at combination antiretroviral
therapy initiation [108].
Recent studies have found that there were frequent
bouts of low-level viremia in human immunodeficiency virus-1 patients on
combination antiretroviral therapy, and that the persistent viremia below 1000
copies/ml also increases risk of virologic failure [109]. A number of factors
have been reported as to be associated with human immunodeficiency virus-1
viral suppression, some of which include the right combination of drug regimen,
fair and good adherence to antiretroviral therapy, WHO stage 1 diagnosis, and
increased treatment duration. It has been suggested that, human
immunodeficiency virus-1 RNA detection during long term combination
antiretroviral therapy indicates drug
resistance and emerging virological failure, which is characterized by repeated
human immunodeficiency virus-1 RNA values of greater than 50-1000copies/ml [110]. To note, high income countries define
virological failure based on viral load thresholds of 50-200 copies per ml,
while for low- income countries, as reported before, WHO guidelines define
virological failure as viral loads of 1000 copies per ml. Increased potential
for human immunodeficiency virus-1 drug resistance, and human immunodeficiency
virus-1 transmission can occur as a result of progression of low-level viremia
to treatment failure. The quality of life in human immunodeficiency virus-1
patients on combination antiretroviral therapy is improved to near normal
levels as combination antiretroviral therapy effectively suppresses human
immunodeficiency virus-1 replication. Unfortunately, for some patients, after
achieving viral suppression, the patients are not able to maintain the
suppression, rather they experience viral rebound, which apart from increasing
the risk of potential for transmission, there is also the risk of treatment
failure.
During combination antiretroviral therapy, detectable
viral load of 50-990copie per ml define low level viremia, and the low level
viremia still occurs in some percentage even after standardized combination antiretroviral
therapy. In their study, reported 26.6% of the sampled patients, had
experienced low level viremia, and had increased risk of virologic
non-suppression and virologic failure. Clinical interventions are initiated in
high income countries upon detection of viral loads that are greater than 50
copies/ml, which may not be the case for resource limited settings. Low level viremia is a risk factor for human
immunodeficiency virus-1 transmission and may impact clinical and immunological
outcomes of patients. Transitioning to DTG reduced the risk of virologic
non-suppression and the subsequent virologic failure. So far, from a global
perspective, only half of the human immunodeficiency virus-1 patients initiated
on antiretroviral therapy have experienced viral suppression. There was low
prevalence of high viral loads and virologic failure in patients who joined
adherence clubs. There is need to establish and expand adherence clubs, and
streamline the models to match the objectives, as well as strengthen adherence
counselling at the various care centers, upon the results of cytokines. Failure
of combination antiretroviral therapy in human immunodeficiency virus-1
patients in low and middle-income countries has been defined by WHO as viral
load of greater than 1000copies /ml. As opposed to blips which are a single
human immunodeficiency virus-1 viral load of more than 50 copies per ml,
followed by virologic suppression, low level viremia is defined by two or more
episodes of human immunodeficiency virus-1 viral load of higher than 50 copies
per ml, and so far, has reported prevalence of between 5% to 30% [111-130].
There is no specific interventions in treatment and monitoring of human
immunodeficiency virus-1 patients even with repeated low level viremia based on
the current WHO guidelines. 10.1% of the 2795 human immunodeficiency virus-1
patients on combination antiretroviral therapy experienced low level viremia
and subsequent virologic failure. To attain viral suppression, it has been
suggested that the patient management could involve good adherence to
counselling strategy and considering nevirapine-based regimens. Studies have
suggested that during combination antiretroviral therapy, detectable viral load
of 50-990copie per ml define low level viremia. Some studies suggest
genotyping, for low level viremia in human immunodeficiency virus-1 patients on
combination antiretroviral therapy, to minimize virologic failure.
Low level viremia while the patient was combination
antiretroviral therapy predicts the risk of virologic failure, and this
suggests frequent viral load monitoring with intensive adherence support.
Because of the increased risk of virologic failure, patients with loe level
viremia may require intensified monitoring. Persistent low level viremia has
been found in human immunodeficiency virus-1 patients on combination
antiretroviral therapy. Risk factors for low level viremia include higher
baseline viral loads, low CD4 + T cell counts prior to combination
antiretroviral therapy, non- nucleoside reverse transcriptase use, and
non-adherence to medication, among other factors. More than half of patients
with persistent viremia exhibit virologic failure. According to WHO guidelines
2016, Virologic failure is persistently detectable VL ? 1000copies/ml in two
consecutive VL measurements within 3 months interval and with adherence, after
at least six months on combination antiretroviral therapy. This study aimed at
investigating the levels of Th17, interferon gamma, CD4+CD25+FoxP3+ T regs and
transforming growth factor beta and viral load in human immunodeficiency
virus-1 infected patients on combination antiretroviral therapy with and
without viremia, attending AMPATH clinic at Moi Teaching and Referral Hospital
-Eldoret, Kenya.
By analyzing the level of cytokines, the study
obtained evidence for varying levels of the target cytokines, suggesting that
the interleukin 17, interferon gamma, interleukin 10, and TGF beta play a
significant role in human immunodeficiency virus-1infection progression. Low level viremia is linked to cytokine
release, and the levels of cytokines predict human immunodeficiency
virus-1replication and progression. There was low level viremia in human
immunodeficiency virus-1patients on combination antiretroviral therapy,
evidenced by the cytokine levels in sampled patients over the study period. The
viral load in low level viremia patients leads to virologic failure. The higher
levels of cytokines in the patients with low level viremia signify viral
replication, and subsequent viral failure. This study suggests that a state of
long-term immune activation is maintained by human immunodeficiency
virus-1infection. The chronic activation results to a general loss of immune
function in T cells that would lead to immune system degradation and subsequent
development of AIDS. There was an imbalance in the proinflammatory and
immunoregulatory cytokines analyzed, a sign that the immune system was trying
to clear an ensued infection, and on the other hand trying to balance the effects
of pro-inflammation by release of the immunoregulatory cytokines, in a bid to
strike some balance. This study demonstrates a strong correlation between human
immunodeficiency virus-1rebound and the levels of both pro-inflammatory and
anti-inflammatory cytokines, as HIV1-1 proliferation seems to affect cytokine
production. Human immunodeficiency virus-1progression may be controlled by a
balance between pro-inflammatory and anti-inflammatory cytokines. The Pro- and
anti-inflammatory cytokines can be used to monitor human immunodeficiency
virus-1disease prognosis during therapy, particularly in low regular viral load
monitoring resource limited settings, to look out for persistent low-level
viremia in the wake of looming virological failure. Therefore, addressing
pro-inflammatory and anti-inflammatory cytokines as significant predictors of
persistent low-level viremia is highly recommended in this study setting.
Monitoring benchmarks for programmes should be revised
for low level viremia, to track human immunodeficiency virus-1progress control
and to strengthen clinical outcomes. Systems should also be designed, for
combination antiretroviral therapy patients to benefit from Supportive services
which may include close monitoring and enhancing patient-physician relationship
as important features to successfully achieving virologic control, and
identifying biomarkers for remission. Other Immune markers investigation should
be considered, to determine utility in monitoring disease progression, thus, an
extensive replica follow-up of this research is needed to validate the
usefulness of interleukin 17, interferon gamma, interleukin 10 , and TGF ? as
predictors of virological failure in persistent low level viremia in human
immunodeficiency virus-1patients on combination antiretroviral therapy.
Additionally, these findings warrant further investigation to incorporate more
cytokines (Both pro-inflammatory and anti-inflammatory), as the conclusions
need to be verified in large, well-designed studies.
None
None