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Understanding Immune Senescence, Exhaustion and Immune Activation in HIV-Tuberculosis Co-Infection

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Human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection accounts for high rates of global morbidity and mortality. Although the pathogeneses of HIV and Mycobacterium tuberculosis (MTB) infections are different, co-existence of both the agents will lead to accentuated disease progression in the host. Expression of markers associated with chronic immune activation, exhaustion and immunosenescence on pathogen-specific CD4+ and CD8+ T cells have been associated with sub-optimal immune responses in HIV-TB co-infection. The effect of chronic immune activation, exhaustion and immunosenescence also appears to extend across distinct sets of immune cells, and hence a wider understanding of the mechanistic aspects underlying these phenomena is urgently required to necessitate the expansion of immune cells with improved functional quality in HIV-TB co-infection. Furthermore, strategies to cause attrition of immunosenescence and immune activation appear to stem from improved understanding of senescence signaling.
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Understanding Immune Senescence,
Exhaustion, and Immune Activation
in HIVTuberculosis Coinfection
Esaki M. Shankar, Alireza Saeidi, Ramachandran Vignesh,
Vijayakumar Velu, and Marie Larsson
Contents
Introduction . . ....................................................................................... 2
Role of HIV in the Exacerbation of MTB Infection .............................................. 3
Impact of M. tuberculosis on the Exacerbation of HIV-1 Infection . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . 4
Immunosenescence ................................................................................. 5
Persistent Infections and Immunosenescence ..................................................... 6
Immunosenescence and HIVM. tuberculosis Coinfection . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
CD38 and HLA-DR Immune Activation Markers in HIVTB Coinfection . . . . . . . . . . . . . . . . . . . . . 7
E.M. Shankar (*)
Division of Infection Biology, Department of Life Sciences, Central University of Tamil Nadu
(CUTN), Thiruvarur, India
Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, Kuala
Lumpur, Malaysia
Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India
e-mail: shankarem@cutn.ac.in
A. Saeidi
Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur,
Malaysia
e-mail: alirezaabc@yahoo.com
R. Vignesh
Laboratory-Based Department, Faculty of Medicine, Royal College of Medicine Universiti Kuala
Lumpur (UniKL-RCMP), Ipoh, Malaysia
e-mail: vignesh@yrgcare.org
V. Velu
Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, GA, USA
e-mail: vvelu@emory.edu
M. Larsson
Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping
University, Linköping, Sweden
e-mail: marie.larsson@liu.se
#Springer International Publishing AG 2018
T. Fulop et al. (eds.), Handbook of Immunosenescence,
https://doi.org/10.1007/978-3-319-64597-1_131-1
1
CD57 and Cellular Immune Senescence . . . . . . . . . . . . . .. . .. . .. . .. . .. . .. . .. . . . .. . .. . .. . .. . .. . .. . .. . 8
MAIT Cells, Tuberculosis, and HIV Infections .................................................. 8
Conclusions ....................................................................................... 10
References . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Abstract
Human immunodeciency virus (HIV) and tuberculosis (TB) coinfection
accounts for high rates of global morbidity and mortality. Although the pathogen-
eses of HIV and Mycobacterium tuberculosis (MTB) infections are different, the
coexistence of both the agents will lead to accentuated disease progression in the
host. Expression of markers associated with chronic immune activation, exhaus-
tion, and immunosenescence on pathogen-specic CD4+ and CD8+ T cells have
been associated with suboptimal immune responses in HIVTB coinfection. The
effect of chronic immune activation, exhaustion, and immunosenescence also
appears to extend across distinct sets of immune cells, and hence a wider under-
standing of the mechanistic aspects underlying these phenomena is urgently
required to necessitate the expansion of immune cells with improved functions
in HIVTB coinfection. Furthermore, strategies to cause attrition of immunose-
nescence and immune activation appear to stem from an improved understanding
of senescence signaling.
Keywords
CD38 · HIVTB · Coinfection · Immune exhaustion · Immunosenescence
Introduction
Human immunodeciency virus (HIV) and tuberculosis (TB) coinfection continues
to account for signicant rates of morbidity and mortality worldwide (Vignesh et al.
2013; Vignesh et al. 2017). Estimates suggest that at the end of 2012, approximately
35.3 million people were living with HIV, of whom ~30% are reported to have been
coinfected with Mycobacterium tuberculosis (M.tuberculosis) (Getahun et al. 2010;
UNAIDS 2013). The burden of HIVTB coinfection is particularly high in the third-
world nations, especially across the Indian subcontinent, South East Asia (SEA), and
sub-Saharan Africa (UNAIDS 2013; WHO 2013). However, we are still in the dawn
of understanding the complex and syndemic interactions between HIV and
M. tuberculosis, which warrants comprehensive investigations to develop effective
therapeutic strategies against HIVTB coinfection. While it is understood that the
pathogenetic bases of HIV and M. tuberculosis infections are different, the coexis-
tence of both the agents in the host will lead to accentuated disease progression.
Although the precise mechanism of copathogenesis still remains unclear, it is widely
believed that this could result from the concurrent depletion of CD4+ T cells by HIV
leading to suboptimal levels of major cytokine growth factors required for the
differentiation and/or expansion of bystander immune cells, especially macrophages
2 E.M. Shankar et al.
and CD8+ T cells, and MTBs ability to infect and kill macrophages in the host,
which conceptually will accelerate the rates of disease progression resulting in
terminal disease. Hence, it is increasingly becoming clear that both HIV and
M. tuberculosis exert considerable inuence on the host immune system.
Role of HIV in the Exacerbation of MTB Infection
TB is one of the most common life-threatening opportunistic infections (OI)
aficting people infected with HIV and accounts for the highest rates of incidence
and mortality among AIDS patients (Kwan and Ernst 2011). Studies have shown that
at the sites of M. tuberculosis presence in the lungs there is evidence of increased HIV
proliferation (Pawlowski et al. 2012), and within activated cells, especially lympho-
cytes and CD14+ macrophages in the pleural space (Lawn et al. 2001) of HIVTB
coinfected subjects. Research suggests that M. tuberculosis triggers HIV-1 multipli-
cation in infected macrophages or T cells (Chetty et al. 2015), and also ex vivo in
alveolar macrophages and lymphocytes of HIV-infected individuals (Pawlowski
et al. 2012). Interestingly, these reports are also reected in vivo where increased
PVLs could be detected in HIV-infected individuals with active TB disease
(Pawlowski et al. 2012). We recently proposed the danger-couplemodel of
HIV/M. tuberculosis disease pathogenesis, wherein we have described the likely
mechanisms of immunopathogenesis in the coinfection scenario (Fig. 1). HIVTB-
coinfected macrophages release low levels of TNF-αand induce less TNF-dependent
apoptosis than those infected only with M. tuberculosis (reviewed in Shankar et al.
2014). Moreover, there is also an evidence for the negative effect of HIVon the ability
of TB-specic T cells to compromise M. tuberculosis establishment. For instance,
there are fewer IFN-γ-producing MTB-specic memory T cells following HIV
infection in patients with latent M. tuberculosis infection. It is also been shown that
M. tuberculosis-specic T cells produce low levels of IFN-γand IL-2 in HIV-infected
individuals than in HIV-uninfected controls with active TB disease (Geldmacher
et al. 2008; Hertoghe et al. 2000; Mendonça et al. 2007). In addition, the immuno-
regulatory cytokine IL-10 is produced in signicantly higher levels in HIVTB
coinfected individuals after M. tuberculosis stimulation, suggesting that chronic
HIV infection could render the CMI ineffective against the tubercle bacilli
(Geldmacher et al. 2010). Furthermore, it is also evident that low levels of IL-2 and
higher macrophage inammatory protein-1β(MIP-1β, also called CCL4) are released
by M. tuberculosisspecic CD4+ T cells in HIV-infected as compared to
HIV-uninfected individuals (Geldmacher et al. 2010). This is reective of HIVs
ability to preferentially infect and deplete IL-2-producing CD4+ T cells, and is
partially inhibited from depleting MIP-1β-producing CD4+ T cells (reviewed in
Shankar et al. 2014). Furthermore, Wax-D on the surface of M. tuberculosis has
been shown to stimulate IL-12 release by macrophages and DCs leading to Th1 cell
expansion, which in turn facilitates HIV establishment (B riken et al. 2004; Salio and
Cerundolo 2015). It is also increasingly becoming clear that coinhibitory molecules
and signs of immune exhaustion and senescence play a signicant role on the
HIVTB Coinfection and Immunosenescence 3
functional quality of T cells in HIVTB coinfection. Increased expression of PD-1 on
T cells of HIVTB coinfected individuals than from TB patients and healthy controls
has been shown (Jurado et al. 2012). Furthermore, HIV infection could also promote
the expansion of T cells coexpressing immune activation markers, namely CD38,
CD70, CD45RO, and HLA-DR, to further exhaust T-cell responses against
M. tuberculosis (Flynn and Chan 2001) (Fig. 1).
Impact of M. tuberculosis on the Exacerbation of HIV-1 Infection
Several investigations on HIV-infected individuals with active TB disease have
reported increased HIV replication and PVL (Goletti et al. 1996) in blood, pulmo-
nary lymphocytes, and alveolar macrophages ex vivo (Goletti et al. 1996; Lawn et al.
2011; Shattock et al. 1993). Increased levels of HIV multiplication has also been
Fig. 1 Proposed model of HIV/Mycobacterium tuberculosis coinfection and immunose-
nescence (Adapted from Shankar et al. 2014). M. tuberculosis and HIV have evolved to coexist
facilitating HIV and TB disease pathogenesis. (a) Resident alveolar macrophages infected with
M. tuberculosis produce high levels of TNF-α, IL-1, and IL-6, resulting in enhanced HIV prolif-
eration. (b)M. tuberculosis elevates CXCR4 expression by alveolar macrophages, which CXCR4-
tropic HIV viruses. (c) Decreased tryptophan levels and eventual increase of IFN-γcould lead
to IDO-mediated suppression of T cells. HIV infection induces expression of immunosenescence
markers, CD38, CD57, CD70, and HLA-DR, weakening T-cell responses against M. tuberculosis.
CXCR4, CX-chemokine receptor 4; DC, dendritic cell; IDO, indoleamine 2,3,dioxygenase; IFN-γ,
interferon gamma; IL, interleukin; HLA-DR, human leukocyte antigen-DR; MФ, macrophage;
MTB, Mycobacterium tuberculosis; PD-1, programmed death-1; Th1, thymus-derived helper T cell;
TNF-α, tumor necrosis factor alpha
4 E.M. Shankar et al.
detected in alveolar macrophages recovered from the BAL uids of HIVTB-
coinfected individuals (Lawn et al. 2011). Wax-D, present in the cell wall of
M. tuberculosis, reportedly activates HIV replication by increasing TNF-αand
IL-6 production by DCs, which could lead to enhanced HIV-1 replication (Briken
et al. 2004). Recently, we proposed a danger-couplemodel of HIVTB coinfection
(Fig. 1), where the mechanisms of T-cell dysfunction in the context of HIV-infection
and the loss of intracellular killing abilities of macrophages harboring
M. tuberculosis have been described. Accordingly, it has become increasingly
clear that M. tuberculosis-infected macrophages containing LAM produce enhanced
levels of TNF-α,IL-1β, and IL-6, causing increased viral replication and HIV
persistence within macrophages. A recent theory suggests that HIV facilitates
MTB persistence within macrophages and provides an opportunity for enhanced
synthesis of IFN-γ, which in turn induces the secretion of indoleamine-pyrrole
2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme leading to T-cell inhibi-
tion (reviewed in Shankar et al. 2014). On the other hand, if IFN-γlevels are not
correlated with IDO secretion by DCs, the role of prostaglandin E2 (PGE2) could be
investigated (von Bergwelt-Baildon et al. 2006). By decreasing available tryptophan
and production of tryptophan metabolites, IDO promotes the inhibition of T-cell
functions and cause immune suppression. Furthermore, there is a recent report that
has correlated poor TB diagnosis with increased IDO levels and decreased trypto-
phan levels in primary TB (Suzuki et al. 2012) (Fig. 1).
Immunosenescence
Senescence is dened as a normal biological process that occurs in all organisms and
is characterized by decline in cellular functions (Bhatia-Dey et al. 2016). Senescence
results from machinery alterations occurring in regulatory molecules in a cell,
especially due to telomere disruption in chromosomes (Montoya-Ortiz 2013). This
process is named as immunosenescence in the context of the immune system and
indicates steady deregulation in immune functions due to natural aging. Roy Walford
was the premiere who used the term immunosenescencein 1969 when he realized
that normal aging causes a stepwise decline in immune functions (Effros 2004).
During immunosenescence, the functions of immune cells are compromised with
age due to which elderly individuals become vulnerable to infectious diseases,
malignancy, and autoimmune disorders (Goronzy and Weyand 2013). Immunose-
nescence leads to phenotypic and functional alterations in T-cell subsets and is often
associated with atrophy of lymphoid organs, eventually leading to declined T- and
B-cell functions (Kaech et al. 2002). However, recent studies suggest that
immunosenescence often involves the T cell compartment leading to compromised
immune responses to antigens and increased rates of expansion of terminally
differentiated T cells (Linton and Dorshkind 2004; Sauce et al. 2009). Immunose-
nescence leads to increased expansion of senescent T cells showing strikingly
HIVTB Coinfection and Immunosenescence 5
signicant ontogenic defects as compared to conventional healthy T cells (Effros
2007). Senile cells also suffer from defective cytokine-secreting abilities and anti-
viral responses, reduce lifespan with shorter telomere lengths, reduce proliferation
abilities, suppress T-cell responses, and show expression of multiple negative
immune checkpoints (reviewed in Shankar et al. 2015). Recently, we also showed
that increased expression of the coinhibitory component 2B4 on iNKT cells led to
poor functional responses and strongly correlated with parameters associated with
HIV disease progression in HIV-infected individuals (Ahmad et al. 2017).
Persistent Infections and Immunosenescence
Evidence suggests that T cells coexpress CD27, CD28, CD57, and CD127 surface
markers in persistent viral infections, especially chronic HCV infection (Barathan
et al. 2016), HIVTB coinfection (Saeidi et al. 2015), as well as CMV and HIV
infections (Kaplan et al. 2011; Scheuring et al. 2002). Hence, persistent viral
infections harness the expansion of senescent T cells via replication senescence
(also called Hayick phenomenon) where the cells show suboptimal or lack of
proliferation abilities and signs of terminal differentiation (Effros and Walford
1984; Hayick and Moorhead 1961). Immunosenescence is also a common phe-
nomenon in younger individuals with underlying malignancies and autoimmune
disorders. Notably, persistent viral infections could cause functional impairment of
Ag-specic T cells including their proliferative potentials (Chou and Effros 2013).
Besides, senescent CD4+ and CD8+ T cells coexpress surface markers (and func-
tional deciencies) that are normally seen in elderly HIV-uninfected individuals
(Deeks and Phillips 2009; Méndez-Lagares et al. 2013; Appay et al. 2007; Desai
and Landay 2010). The persistence of immune activation is remarkable in chronic
HIV disease, both in HIV disease as well as infection/coinfection with HBV, HCV,
and M. tuberculosis (reviewed in Shankar et al. 2015; Yong et al. 2017).
Immunosenescence is characterized by the upregulation of activation markers,
especially CD38, CD69, and HLA-DR on pathogen-specic CD4+ and CD8+ T
cells (Cao et al. 2009; Czesnikiewicz-Guzik et al. 2008). Of these, CD38 has also
been claimed to be a marker of HIV disease progression and mortality (Liu et al.
1997). Furthermore, monocytes, DCs, and natural killer (NK) cells also have been
shown to express immune activation markers apart from classical T cells (Kamat
et al. 2012). One of the key predictors of HIV disease progression is increased signs
of immune activation on T cells (Wilson et al. 2004). This could be partly explained
because sustained activation accelerates the rate of disease progression often by
impairing the ability of the immune system to recognize microbial antigens
(Gonzalez et al. 2009). Besides, it has been shown that sustained activation also
indirectly predicts progression to non-AIDS-associated mortality (Deeks and Phil-
lips 2009). Increased expression of CD57 expression has also been linked to ablation
of CD127 expression, leading to functional T-cell defects and senescence (Brenchley
et al. 2003; Kaplan et al. 2011; Kiazyk and Fowke 2008; Mojumdar et al. 2011).
6 E.M. Shankar et al.
Immunosenescence and HIVM. tuberculosis Coinfection
While the association of HIVTB is apparently clear, the likely mechanisms behind
such a syndemic relationship still remain unanswered although both HIV and
M. tuberculosis exert a negative impact on the host immune system (reviewed in
Shankar et al. 2015). Several investigations have shown that persistent HIV disease
facilitates the onset of CIA and as a result to premature senescence (Dock and Effros
2011; Effros 2007; Gonzalez et al. 2009; Papagno et al. 2004). An existing hypoth-
esis suggests that MTB infection exacerbates HIV disease by increasing the likeli-
hood of viral transmission as a result of alternations in signal transduction, cytokine
modulation; overcoming of antiviral responses by overwhelming HIV-inducing
responses; and promoting of HIV amplication by facilitating the assembly of
granuloma (Diedrich and Flynn 2011; Kwan and Ernst 2011; Pawlowski et al.
2012). The upregulation of immunosenescence markers on T cells apparently leads
to the decline in the frequency of functional T cells, accelerating a shift to expansion
of terminally differentiated T cells with altered functions (Larbi and Fulop 2014),
and therefore, it is possible to associate immunosenescence and immune activation
with HIVTB coinfection (Shankar et al. 2015).
CD38 and HLA-DR Immune Activation Markers in HIVTB
Coinfection
CD38 and HLA-DR are classical immune activation markers expressed on a plethora
of immune cells, especially following their activation. Besides, several other markers
have also been reported including CD27, CD28, Ki-67, and CD69 (Cao et al. 2009;
Czesnikiewicz-Guzik et al. 2008). CD38 is a cyclic ADP ribose hydrolase that plays
a key role in signal transduction and calcium mobilization during T-cell activation
(Kestens et al. 1992). The MHC class II cell surface ligand HLA-DR presents
peptide antigens to APCs and is a marker of immune activation on T cells (Effros
et al. 1983; Kestens et al. 1994). Increased expression of these immune activation
markers is clearly reective of HIV disease progression (Hazenberg et al. 2003; Liu
et al. 1997,1998; Sousa et al. 2002; Mocroft et al. 1997).
Several reports have shown that coinfection with HBV, HCV, and M. tuberculosis
can directly impact HIV disease progression via increased T-cell activation (Borkow
et al. 2001). Higher levels of CD38 expression on CD4+ and CD8+ T cells of
HIVTB-coinfected individuals is comparable with HIV infection (Borkow et al.
2001; Rodrigues et al. 2002). This is also consistent with sustained levels of periph-
eral immune activation following pathogenic persistence especially in the context of
HIVTB coinfection (reviewed in Shankar et al. 2015). CD38 expression on CD4+
and CD8+ T cells has also been inversely associated with CD8+ T-cell counts and
HIV PVL (Saeidi et al. 2015), and increased levels of CD38 could accelerate the rates
of HIV disease progression (Rosenberg et al. 1997). A 19 kD lipoprotein and
lipoprotein Rg of M. tuberculosis have been identied to increase the expression
levels of HLA-DR on DCs and macrophages, leading to impaired antigen presenta-
tion to T cells (Gehring et al. 2003; Simmons et al. 2010).
HIVTB Coinfection and Immunosenescence 7
CD57 and Cellular Immune Senescence
CD57 is a classical marker of replicative senescence in CD4+ and CD8+ Tcells, and
their expression correlates with aging and infection with persistent pathogens
(Brenchley et al. 2003; Palmer et al. 2005). Cells showing concurrent increase of
CD57 and decrease of CD28 are classied as late-differentiated or senescent cells.
However, some investigators have suggested that CD57 and CD27 could be a highly
relevant correlate as compared to CD28 as an indicator of replicative senescence
(Appay and Rowland-Jones 2004; Larbi and Fulop 2014), and therefore the loss of
CD27 and CD28 expressions with concurrent upregulation of CD57 is a clear
indication of replicative senescence (Palmer et al. 2005; Papagno et al. 2004; Weekes
et al. 1999). Hence, based on differential expression of senescence/costimulatory
molecules, T cells are classied into early (CD57CD28/CD27+), intermediate
(CD57CD28/CD27), and late senescent T cells (CD57+ CD28/CD27).
Accordingly, while HIVTB coinfection has been shown to render the expansion
of late (CD57+ CD28/CD27) senescent CD8+ T cells (CD57CD28/CD27+),
HIV infection has been found to present intermediate-senescent CD8+ T cells
(CD57CD28/CD27). Late-senescent CD8+ T cells predominantly seen in
HIVTB coinfection reportedly have declined telomerase activity (Pantaleo and
Koup 2004). Besides replicative senescence, CD57 is believed to play a key role
in programmed cell death, activation-induced cell death (AICD), cytokine responses,
and cytolysin functions in infections and malignant conditions (Focosi et al. 2010).
Given that CD8+ T cells are key to killing of HIV-infected CD4+ T cells and other
HIV reservoirs, CD8+ T cells have been shown to express high levels of CD57 in
HIVTB coinfection together with functional decits (Brenchley et al. 2003).
MAIT Cells, Tuberculosis, and HIV Infections
Mucosal-associated invariant T (MAIT) cells represent a unique subset of innate-like
T cells (Tilloy et al. 1999) and play an important role in the hosts innate defense
attributes (Le Bourhis et al. 2010). MAIT cells constitute ~5% of the total T-cell
pool (Ussher et al. 2014) and ~1/3rd of the CD8+ T-cell pool in the blood of
healthy individuals (Saeidi et al. 2015). These cells express a semi-invariant
Vα7.2-Jα33/12/20 TCR (Huang et al. 2008; Lepore et al. 2014) that predominantly
recognize bacterial and fungal antigens presented on an evolutionarily conserved
MHC class I-related (MR1) molecule (Billerbeck et al. 2010; Le Bourhis et al. 2010).
MAIT cells express CD161 (Fergusson et al. 2014; Martin et al. 2009), based on
which these cells are classied into CD161, CD161+, and CD161++ subsets (Gold
et al. 2010). MAIT cells also express CCR6, CCR5, CCR9, and CXCR6 that localize
these cells prominently to the lungs and liver (Dusseaux et al. 2011). MAIT cells can
be activated by bacteria via their riboavin metabolites or by exposure to IL-12 and
IL-18 as these cells express levels of IL-12 and IL-18 receptors (Le Bourhis et al.
2013; Napier et al. 2015).
8 E.M. Shankar et al.
M. tuberculosis infection is a classic example where extensive investigations have
been done to unveil the roles of MAIT cells (Gold et al. 2010; Harriff et al. 2014).
There is ample evidence on the enrichment of MAIT cells across the pulmonary
compartment of healthy individuals, suggesting the early response of these cells
during infection (Gold et al. 2010). Patients with M. tuberculosis infections have
lower frequency of peripheral MAIT cells (Kwon et al. 2015; Le Bourhis et al. 2010),
and this decline is attributed to their trafcking from the systemic circulation into the
lungs, where exposure to M. tuberculosis likely occurs via the respiratory airway,
which leads to MAIT cell decline in the peripheral compartment (Gold et al. 2010).
In HIV infection, MAIT cell levels reportedly undergo depletion by week 23 after
initial HIV infection (Wong et al. 2013). In regard to senescence, the expression of
CD38, HLA-DR, and CD57 are reportedly increased on MAIT cells in chronically
HIV-infected patients (Leeansyah et al. 2013). In addition, the frequency of MAIT
cells had a negative correlation with CD38 expression on MAIT cells as well as on
total CD8+ T cells (Leeansyah et al. 2013). Further, the long-term ART could
decrease HLA-DR expression on MAIT cells but does not affect the expressions
of CD38 and CD57 (Leeansyah et al. 2013). The upregulation of CD69 on MAIT
cells has also been reported in HIV infection (Leeansyah et al. 2015). MAIT cells
from patients with active TB showed increased expression of PD-1, and blockade of
the PD-1 signaling pathway remarkably improved MAIT cell cytokine production in
response to antigen activation (Jiang et al. 2014). The phenotype of an exhausted
MAIT cell is shown in Fig. 2. We recently showed that PD-1 is highly expressed on
MAIT cells in the peripheral blood of HIV-infected and HIVM. tuberculosis-
coinfected patients and that cART +/ATT failed to reduce the elevated PD-1
expression (Saeidi et al. 2015). However, the roles of immunosenescence, chronic
immune activation, and immune exhaustion are still in the infancy stages and much
Fig. 2 Phenotype of an
exhausted MAIT cell. MAIT
cells appear to express high
levels of CD57, HLA-DR, and
CD38 in HIVTB coinfection
although their roles on the
functional aspects of these
cells are currently being
extensively investigated
(Saeidi et al. 2016). Abnormal
expression pattern of
transcription factors T-bet and
EOMES is believed to result
in insufciency of cytotoxic
functions and cytokine
production by MAIT cells
HIVTB Coinfection and Immunosenescence 9
requires to be done to explore the mechanistic bases on MAIT cell depletion and
their likely association with immunosenescence in HIVM. tuberculosis
coinfection.
Conclusions
The mechanistic aspects of immunosenescence, exhaustion, and immune activation
in HIVTB coinfection are complex as both the pathogens play a signicant role in
accelerating the disease progressions of each disease, and strategies to cause the
attrition of signs of immunosenescence and immune activation appear to stem from
improved understanding of senescence signaling to render the identication of
biological intervention measures to improve the quality of life of HIVTB-
coinfected individuals. Immunosenescence, immune exhaustion and chronic
immune activation appears to have a wider distribution across several phenotypes
of immune cells in HIV-TB co-infection contrary to how it was thought earlier, and
hence measures to negate the effects of such deleterious signaling pathways is
urgently required to improve healthy immune responses against the challenges
posed by chronic infectious agents. Further, sustenance of molecules associated
with T-cell survival and proliferation of pathogen-specic T cells and MAIT cells
is paramount key to improved functional immune responses. The development of
immunotherapeutic molecules to restore immune functions is reliant on the ablation
of immunosenescence molecules, especially in the context of HIVTB coinfection,
and requires extensive investigation.
Acknowledgments Support is acknowledged from the High Impact Research (HIR) (UM.
C.625/1/HIR/139), and University of Malaya Research Grants RP021A-13HTM and RG448-
12HTM of the Health and Translational Medicine Research Cluster to Esaki M. Shankar. Marie
Larsson was supported by Swedish Research Council Grant AI52731, the Swedish Physicians
against AIDS Research Foundation, the Swedish International Development Cooperation Agency,
the Swedish International Development Cooperation Agency Special Assistant to the Resident
Coordinator, VINNMER for Vinnova, the Linköping University Hospital Research Fund, CALF,
and by the Swedish Society of Medicine. We also acknowledge NIH/NIAID grant support
1U19AI109633-01 to Vijayakumar Velu.
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