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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
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
A. Saeidi
Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur,
R. Vignesh
Laboratory-Based Department, Faculty of Medicine, Royal College of Medicine Universiti Kuala
Lumpur (UniKL-RCMP), Ipoh, Malaysia
V. Velu
Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, GA, USA
M. Larsson
Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping
University, Linköping, Sweden
#Springer International Publishing AG 2018
T. Fulop et al. (eds.), Handbook of Immunosenescence,
CD57 and Cellular Immune Senescence . . . . . . . . . . . . . .. . .. . .. . .. . .. . .. . .. . . . .. . .. . .. . .. . .. . .. . .. . 8
MAIT Cells, Tuberculosis, and HIV Infections .................................................. 8
Conclusions ....................................................................................... 10
References . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
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.
CD38 · HIVTB · Coinfection · Immune exhaustion · Immunosenescence
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).
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
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
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.
Ahmad F, Shankar EM, Yong YK, Tan HY, Ahrenstorf G, Jacobs R, Larsson M (2017) Negative
checkpoint regulatory molecule 2B4 (CD244) upregulation is associated with invariant natural
killer T cell alterations and human immunodeciency virus disease progression. Front Immunol
Appay V, Rowland-Jones SL (2004) Lessons from the study of T-cell differentiation in persistent
human virus infection. Semin Immunol 16(3):205212
Appay V, Almeida JR, Sauce D, Autran B, Papagno L (2007) Accelerated immune senescence and
HIV-1 infection. Exp Gerontol 42(5):432437
10 E.M. Shankar et al.
Barathan M, Mohamed R, Vadivelu J, Chang LY, Saeidi A, Yong YK, Shankar EM (2016)
Peripheral loss of CD8+ CD161++ TCRVα72+ mucosal-associated invariant T cells in chronic
hepatitis C virus-infected patients. Eur J Clin Invest 46(2):170180
Bhatia-Dey N, Kanherkar RR, Stair SE, Makarev EO, Csoka AB (2016) Cellular senescence as the
causal nexus of aging. Front Genet 12;7:13
Billerbeck E, Kang YH, Walker L, Lockstone H, Grafmueller S, Fleming V, Ramamurthy N (2010)
Analysis of CD161 expression on human CD8+ T cells denes a distinct functional subset with
tissue-homing properties. Proc Natl Acad Sci U S A 107(7):30063011
Borkow G, Weisman Z, Leng Q, Stein M, Kalinkovich A, Wolday D, Bentwich Z (2001)
Helminths, human immunodeciency virus and tuberculosis. Scand J Infect Dis 33(8):568571
Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Roederer M (2003)
Expression of CD57 denes replicative senescence and antigen-induced apoptotic death of
CD8+ T cells. Blood 101(7):27112720
Briken V, Porcelli SA, Besra GS, Kremer L (2004) Mycobacterial lipoarabinomannan and
related lipoglycans: from biogenesis to modulation of the immune response. Mol Microbiol
Cao W, Jamieson BD, Hultin LE, Hultin PM, Detels R (2009) Regulatory T cell expansion and
immune activation during untreated HIV type 1 infection are associated with disease progres-
sion. AIDS Res Hum Retroviruses 25(2):183191
Chetty S, Govender P, Zupkosky J, Pillay M, Ghebremichael M, Moosa MYS, Kasprowicz VO
(2015) Co-infection with Mycobacterium tuberculosis impairs HIV-specic CD8+ and CD4+
T cell functionality. PLoS One 10(3):e0118654
Chou JP, Effros RB (2013) T cell replicative senescence in human aging. Curr Pharm Des
Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Goronzy JJ (2008)
T cell subset-specic susceptibility to aging. Clin Immunol 127(1):107118
Deeks SG, Phillips AN (2009) Clinical review: HIV infection, antiretroviral treatment, ageing, and
non-AIDS related morbidity. BMJ 338:288292
Desai S, Landay A (2010) Early immune senescence in HIV disease. Curr HIV/AIDS Rep
Diedrich CR, Flynn JL (2011) HIV-1/mycobacterium tuberculosis coinfection immunology: how
does HIV-1 exacerbate tuberculosis? Infect Immun 79(4):14071417
Dock JN, Effros RB (2011) Role of CD8 T cell replicative senescence in human aging and in
HIV-mediated immunosenescence. Aging Dis 2(5):382
Dusseaux M, Martin E, Serriari N, Péguillet I, Premel V, Louis D, Lantz O (2011) Human
MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17secreting T cells. Blood
Effros RB (2004) From Hayick to Walford: the role of T cell replicative senescence in human
aging. Exp Gerontol 39(6):885890
Effros RB (2007) Role of T lymphocyte replicative senescence in vaccine efcacy. Vaccine
Effros RB, Walford RL (1984) T cell cultures and the Hayick limit. Hum Immunol 9(1):4965
Effros RB, Dillard L, Zeller E, Naeim F, Walford RL (1983) Strong HLA-DR expression in T cell
cultures after activation is necessary for IL-2-dependent proliferation. Hum Immunol
Fergusson JR, Smith KE, Fleming VM, Rajoriya N, Newell EW, Simmons R, Kurioka A (2014)
CD161 denes a transcriptional and functional phenotype across distinct human T cell lineages.
Cell Rep 9(3):10751088
Flynn JL, Chan J (2001) Immunology of tuberculosis. Annu Rev Immunol 19(1):93129
Focosi D, Bestagno M, Burrone O, Petrini M (2010) CD57+ T lymphocytes and functional immune
deciency. J Leukoc Biol 87(1):107116
Gehring AJ, Rojas RE, Canaday DH, Lakey DL, Harding CV, Boom WH (2003) The
Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits gamma interferon-regulated
HIVTB Coinfection and Immunosenescence 11
HLA-DR and FcγR1 on human macrophages through Toll-like receptor 2. Infect Immun
Geldmacher C, Schuetz A, Ngwenyama N, Casazza JP, Sanga E, Saathoff E, Minja F (2008) Early
depletion of Mycobacterium tuberculosis-specic T helper 1 cell responses after HIV-1 infec-
tion. J Infect Dis 198(11):15901598
Geldmacher C, Ngwenyama N, Schuetz A, Petrovas C, Reither K, Heeregrave EJ, Pollakis G
(2010) Preferential infection and depletion of Mycobacterium tuberculosisspecic CD4 T cells
after HIV-1 infection. J Exp Med 207(13):28692881
Getahun H, Gunneberg C, Granich R, Nunn P (2010) HIV infection associated tuberculosis: the
epidemiology and the response. Clin Infect Dis 50(Suppl 3):S201S207
Gold MC, Cerri S, Smyk-Pearson S, Cansler ME, Vogt TM, Delepine J, Lantz O (2010) Human
mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol 8(6):e1000407
Goletti D, Weissman D, Jackson RW, Graham NM, Vlahov D, Klein RS, Fauci AS (1996) Effect
of Mycobacterium tuberculosis on HIV replication. Role of immune activation. J Immunol
Gonzalez VD, Falconer K, Blom KG, Reichard O, Mørn B, Laursen AL, Sandberg JK (2009) High
levels of chronic immune activation in the T-cell compartments of patients coinfected with
hepatitis C virus and human immunodeciency virus type 1 and on highly active antiretroviral
therapy are reverted by alpha interferon and ribavirin treatment. J Virol 83(21):1140711411
Goronzy JJ, Weyand CM (2013) Understanding immunosenescence to improve responses to
vaccines. Nat Immunol 14(5):428436
Harriff MJ, Cansler ME, Toren KG, Caneld ET, Kwak S, Gold MC, Lewinsohn DM (2014)
Human lung epithelial cells contain Mycobacterium tuberculosis in a late endosomal vacuole
and are efciently recognized by CD8+ T cells. PLoS One 9(5):e97515
Hayick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res
Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, Lange JM, Miedema F (2003)
Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS
Hertoghe T, Wajja A, Ntambi L, Okwera A, Aziz MA, Hirsch C, Colebunders R (2000) T cell
activation, apoptosis and cytokine dysregulation in the (co) pathogenesis of HIV and pulmonary
tuberculosis (TB). Clin Exp Immunol 122(3):350357
Huang S, Gilllan S, Kim S, Thompson B, Wang X, Sant AJ, Hansen TH (2008) MR1 uses
an endocytic pathway to activate mucosal-associated invariant T cells. J Exp Med
Jiang J, Wang X, An H, Yang B, Cao Z, Liu Y, Cheng X (2014) Mucosal-associated invariant T-cell
function is modulated by programmed death-1 signaling in patients with active tuberculosis. Am
J Respir Crit Care Med 190(3):329339
Jurado JO, Pasquinelli V, Alvarez IB, Martínez GJ, Laufer N, Sued O, Quiroga MF (2012) ICOS,
SLAM and PD-1 expression and regulation on T lymphocytes reect the immune dysregulation
in patients with HIV-related illness with pulmonary tuberculosis. J Int AIDS Soc 15(2):17428
Kaech SM, Wherry EJ, Ahmed R (2002) Effector and memory T-cell differentiation: implications
for vaccine development. Nat Rev Immunol 2(4):251262
Kamat A, Misra V, Cassol E, Ancuta P, Yan Z, Li C, Gabuzda D (2012) A plasma biomarker
signature of immune activation in HIV patients on antiretroviral therapy. PLoS One 7(2):e30881
Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, Hodis HN (2011) T cell
activation and senescence predict subclinical carotid artery disease in HIV-infected women.
J Infect Dis 203(4):452463
Kestens L, Vanham G, Gigase P, Young G, Hannet I, Vanlangendonck F, Bach BA (1992)
Expression of activation antigens, HLA-DR and CD38, on CD8 lymphocytes during HIV-1
infection. AIDS 6(8):793798
12 E.M. Shankar et al.
Kestens L, Vanham G, Vereecken C, Vandenbruaene M, Vercauteren G, Colebunders RL,
Gigase PL (1994) Selective increase of activation antigens HLA-DR and CD38 on CD45RO+
T lymphocytes during HIV-1 infection. Clin Exp Immunol 95(3):436441
Kiazyk SAK, Fowke KR (2008) Loss of CD127 expression links immune activation and CD4+
T cell loss in HIV infection. Trends Microbiol 16(12):567573
Kwan CK, Ernst JD (2011) HIV and tuberculosis: a deadly human syndemic. Clin Microbiol Rev
Kwon YS, Cho YN, Kim MJ, Jin HM, Jung HJ, Kang JH, Kee SJ (2015) Mucosal-associated
invariant T cells are numerically and functionally decient in patients with mycobacterial
infection and reect disease activity. Tuberculosis 95(3):267274
Larbi A, Fulop T (2014) From truly naïveto exhausted senescentT cells: when markers predict
functionality. Cytometry A 85(1):2535
Lawn SD, Pisell TL, Hirsch CS, Wu M, Butera ST, Toossi Z (2001) Anatomically compartmental-
ized human immunodeciency virus replication in HLA-DR+ cells and CD14+ macrophages at
the site of pleural tuberculosis coinfection. J Infect Dis 184(9):11271133
Lawn SD, Brooks SV, Kranzer K, Nicol MP, Whitelaw A, Vogt M, Wood R (2011) Screening for
HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the
Xpert MTB/RIF assay: a prospective study. PLoS Med 8(7):e1001067
Le Bourhis L, Martin E, Péguillet I, Guihot A, Froux N, Coré M, Ngo C (2010) Antimicrobial
activity of mucosal-associated invariant T cells. Nat Immunol 11(8):701708
Le Bourhis L, Dusseaux M, Bohineust A, Bessoles S, Martin E, Premel V, Hivroz C (2013) MAIT
cells detect and efciently lyse bacterially-infected epithelial cells. PLoS Pathog 9(10):
Leeansyah E, Ganesh A, Quigley MF, Sönnerborg A, Andersson J, Hunt PW, Shacklett BL (2013)
Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell
population in chronic HIV-1 infection. Blood 121(7):11241135
Leeansyah E, Svärd J, Dias J, Buggert M, Nyström J, Quigley MF, Sandberg JK (2015) Arming of
MAIT cell cytolytic antimicrobial activity is induced by IL-7 and defective in HIV-1 infection.
PLoS Pathog 11(8):e1005072
Lepore M, Kalinichenko A, Colone A, Paleja B, Singhal A, Tschumi A, Sander P (2014) Parallel
T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ
repertoire. Nat Commun 5:3866
Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat
Immunol 5(2):133139
Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, Giorgi JV (1997) Elevated CD38 antigen
expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression
to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble
immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir
Immune Dec Syndr Hum Retrovirol 16(2):8392
Liu Z, Cumberland WG, Hultin LE, Kaplan AH, Detels R, Giorgi JV (1998) CD8+ T-lymphocyte
activation in HIV-1 disease reects an aspect of pathogenesis distinct from viral burden and
immunodeciency. J Acquir Immune Dec Syndr Hum Retrovirol 18(4):332340
Martin E, Treiner E, Duban L, Guerri L, Laude H, Toly C, Cherif S (2009) Stepwise development of
MAIT cells in mouse and human. PLoS Biol 7(3):e1000054
Méndez-Lagares G, Díaz L, Correa-Rocha R, León Leal JA, Ferrando-Martínez S, Ruiz-Mateos E,
Leal M (2013) Specic patterns of CD4-associated immunosenescence in vertically
HIV-infected subjects. Clin Microbiol Infect 19(6):558565
Mendonça M, Tanji MM, Silva LC, Silveira GG, Oliveira SC, Duarte AJ, Benard G (2007)
Decient in vitro anti-mycobacterial immunity despite successful long-term highly active
antiretroviral therapy in HIV-infected patients with past history of tuberculosis infection or
disease. Clin Immunol 125(1):6066
HIVTB Coinfection and Immunosenescence 13
Mocroft A, Boll M, Lipman M, Medina E, Borthwick N, Timms A, Lee CA (1997) CD8+, CD38+
lymphocyte percent: a useful immunological marker for monitoring HIV-1-infected patients.
J Acquir Immune Dec Syndr Hum Retrovirol 14(2):158162
Mojumdar K, Vajpayee M, Chauhan NK, Singh A, Singh R, Kurapati S (2011) Loss of CD127 &
increased immunosenescence of T cell subsets in HIV infected individuals. Indian J Med Res
Montoya-Ortiz G (2013) Immunosenescence, aging, and systemic lupus erythematous.
Autoimmune Dis 2013:267078
Napier RJ, Adams EJ, Gold MC, Lewinsohn DM (2015) The role of mucosal associated invariant
T cells in antimicrobial immunity. Front Immunol 6:344
Palmer BE, Blyveis N, Fontenot AP, Wilson CC (2005) Functional and phenotypic characterization
of CD57+ CD4+ T cells and their association with HIV-1-induced T cell dysfunction. J Immunol
Pantaleo G, Koup RA (2004) Correlates of immune protection in HIV-1 infection: what we know,
what we dont know, what we should know. Nat Med 10(8):806810
Papagno L, Spina CA, Marchant A, Salio M, Rufer N, Little S, Dunbar PR (2004) Immune
activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol
Pawlowski A, Jansson M, Sköld M, Rottenberg ME, Källenius G (2012) Tuberculosis and HIV
co-infection. PLoS Pathog 8(2):e1002464
Rodrigues DS, Medeiros EA, Weckx LY, Bonnez W, Salomão R, Kallas EG (2002)
Immunophenotypic characterization of peripheral T lymphocytes in Mycobacterium tuberculo-
sis infection and disease. Clin Exp Immunol 128(1):149154
Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD (1997)
Vigorous HIV-1-specic CD4+ T cell responses associated with control of viremia. Science
Saeidi A, Ellegård R, Yong YK, Tan HY, Velu V, Ussher JE, Larsson M (2016) Functional role of
mucosal-associated invariant T cells in HIV infection. J Leukoc Biol 100(2):30514
Saeidi A, Tien VLT, Al-Batran R, Al-Darraji HA, Tan HY, Yong YK, Velu V (2015) Attrition of
TCR Vα7.2+ CD161++ MAIT cells in HIV-tuberculosis co-infection is associated with elevated
levels of PD-1 expression. PLoS One 10(4):e0124659
Salio M, Cerundolo V (2015) Regulation of lipid specic and vitamin specic non-MHC restricted
T cells by antigen presenting cells and their therapeutic potentials. Front Immunol 6:388
Sauce D, Larsen M, Fastenackels S, Duperrier A, Keller M, Grubeck-Loebenstein B, Appay V
(2009) Evidence of premature immune aging in patients thymectomized during early childhood.
J Clin Invest 119(10):30703078
Scheuring UJ, Sabzevari H, Theolopoulos AN (2002) Proliferative arrest and cell cycle regulation
in CD8+ CD28versus CD8+ CD28+ T cells. Hum Immunol 63(11):10001009
Shankar EM, Vignesh R, EllegAard R, Barathan M, Chong YK, Bador MK, Larsson M (2014)
HIVMycobacterium tuberculosis co-infection: a danger-couple modelof disease pathogen-
esis. Pathog Dis 70(2):110118
Shankar EM, Velu V, Kamarulzaman A, Larsson M (2015) Mechanistic insights on immunose-
nescence and chronic immune activation in HIV-tuberculosis co-infection. World J Virol 4(1):17
Shattock RJ, Friedland JS, Grifn GE (1993) Modulation of HIV transcription in and release from
human monocytic cells following phagocytosis of Mycobacterium tuberculosis. Res Virol
Simmons DP, Canaday DH, Liu Y, Li Q, Huang A, Boom WH, Harding CV (2010) Mycobacterium
tuberculosis and TLR2 agonists inhibit induction of type I IFN and class I MHC antigen cross
processing by TLR9. J Immunol 185(4):24052415
Sousa AE, Carneiro J, Meier-Schellersheim M, Grossman Z, Victorino RM (2002) CD4 T cell
depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but
only indirectly to the viral load. J Immunol 169(6):34003406
14 E.M. Shankar et al.
Suzuki Y, Suda T, Asada K, Miwa S, Suzuki M, Fujie M, Hayakawa H (2012) Serum indoleamine
2, 3-dioxygenase activity predicts prognosis of pulmonary tuberculosis. Clin Vaccine Immunol.
Tilloy F, Treiner E, Park SH, Garcia C, Lemonnier F, De La Salle H, Lantz O (1999) An invariant
T cell receptor αchain denes a novel TAP-independent major histocompatibility complex class
Ibrestricted α/βT cell subpopulation in mammals. J Exp Med 189(12):19071921
UNAIDS (2013) Global report: UNAIDS report on the global AIDS epidemic 2013. UNAIDS.
Ussher JE, Klenerman P, Willberg CB (2014) Mucosal-associated invariant T-cells: new players in
anti-bacterial immunity. Front Immunol 5:450
Vignesh R, Kumarasamy N, Lim A, Solomon S, Murugavel KG, Balakrishnan P, Solomon SS
(2013) TB-IRIS after initiation of antiretroviral therapy is associated with expansion of preex-
istent Th1 responses against Mycobacterium tuberculosis antigens. J Acquir Immune Dec
Syndr 64(3):2418
Vignesh R, Swathirajan CR, Solomon SS, Shankar EM, Murugavel KG (2017) Risk factors and
frequency of tuberculosis-associated immune reconstitution inammatory syndrome among
HIV/tuberculosis co-infected patients in Southern India. Indian J Med Microbiol 35(2):279281
von Bergwelt-Baildon MS, Popov A, Saric T, Chemnitz J, Classen S, Stoffel MS, Wickenhauser C
(2006) CD25 and indoleamine 2, 3-dioxygenase are up-regulated by prostaglandin E2 and
expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibi-
tion. Blood 108(1):228237
Weekes MP, Wills MR, Mynard K, Hicks R, Sissons JG, Carmichael AJ (1999) Large clonal
expansions of human virus-specic memory cytotoxic T lymphocytes within the CD57+
CD28CD8+ T-cell population. Immunology 98(3):443449
Wilson CM, Ellenberg JH, Douglas SD, Moscicki AB, Holland CA, Reach Project of the Adoles-
cent Medicine HIV/AIDS Research Network (2004) CD8+ CD38+ T cells but not HIV type
1 RNA viral load predict CD4+ T cell loss in a predominantly minority female HIV+ adolescent
population. AIDS Res Hum Retroviruses 20(3):263269
Wong EB, Akilimali NA, Govender P, Sullivan ZA, Cosgrove C, Pillay M, Klenerman P (2013)
Low levels of peripheral CD161++ CD8+ mucosal associated invariant T (MAIT) cells are
found in HIV and HIV/TB co-infection. PLoS One 8(12):e83474
World Health Organization (2013) Global tuberculosis report 2013. World Health Organization,
Yong YK, Tan HY, Saeidi A, Rosmawati M, Atiya N, Ansari AW, Rajarajeswaran J (2017)
Decrease of CD69 levels on TCR Vα7.2+CD4+ innate-like lymphocytes is associated with
impaired cytotoxic functions in chronic hepatitis B virus-infected patients. Innate Immun 23
HIVTB Coinfection and Immunosenescence 15
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Hepatitis B virus (HBV) infection is a major cause of chronic liver disease that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses represent the key determinants of HBV clearance or persistence. Here, we investigated the role of the early activation marker, CD69 and effector cytokines, granzyme B (GrB), and interferon-gamma (IFN-) in the exhaustion of innate-like TCR Va7.2+CD4+T cells, in 15 individuals with chronic HBV (CHB) infection where 6 were HBV DNA+ and 9 were HBV DNA-. HBV plasma viral loads were measured using a commercial COBAS AmpliPrep-COBAS TaqMan HBV test. The percentage of cytokine-producing T cells and MAIT cells were significantly perturbed in HBV patients relative to healthy controls (HCs, n=11). The intracellular expression of GrB, and IFN- was significantly reduced in MAIT cells derived from HBV-infected patients as compared to HCs, and the levels correlated with the percentage and levels (MFI) of CD69 expression. The total expression of CD69 (iMFI) was lower in CHB patients as compared to HCs. The frequency of CD69+ cells correlated with the levels of cytokine expression (MFI), particularly in CHB patients as compared to HCs. In summary, the polyfunctionality of peripheral T cells was significantly reduced among CHB patients, especially in the TCR Va7.2+CD4+ T cells, and the levels of cytokine expression correlated with functional cytokine levels.
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Immune reconstitution inflammatory syndrome (IRIS) continues to be a complication in HIV/tuberculosis (TB) co‑infected patients initiating highly active antiretroviral therapy (HAART). The aim of this study was to evaluate the risk factors associated with developing IRIS to identify a possible biomarker to predict or diagnose IRIS in patients initiating HAART. A total of 175 HIV/TB co-infected patients initiating HAART were followed up longitudinally during September 2010 to May 2013 attending a HIV care clinic in Chennai. Patients were followed up longitudinally after HAART initiation and baseline demographic, laboratory parameters and treatment characteristics between patients with IRIS events and those without IRIS events were compared. Chi-square or Fisher’s exact test for categorical variables and a Wilcoxon rank-sum test for continuous variables were performed using SPSS, version 12.0 software. Patients with IRIS had a significantly lower median baseline CD4+ T-cell count (P = 0.0039). There were no differences in terms of sex, CD4 T-cell %, plasma viral load, time interval between initiating ATT and HAART between the IRIS and non-IRIS patients. Low CD4+ T-cell count (<100 cells/µL) could be used as a marker to screen and monitor patients initiating HAART.
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The CD1d-restricted invariant natural killer T (iNKT) cells are implicated in innate immune responses against human immunodeficiency virus (HIV). However, the determinants of cellular dysfunction across the iNKT cells subsets are seldom defined in HIV disease. Herein, we provide evidence for the involvement of the negative checkpoint regulator (NCR) 2B4 in iNKT cell alteration in a well-defined cohort of HIV-seropositive anti-retroviral therapy (ART) na?ve, ART-treated, and elite controllers (ECs). We report on exaggerated 2B4 expression on iNKT cells of HIV-infected treatment-na?ve individuals. In sharp contrast to CD4?iNKT cells, 2B4 expression was significantly higher on CD4+ iNKT cell subset. Notably, an increased level of 2B4 on iNKT cells was strongly correlated with parameters associated with HIV disease progression. Further, iNKT cells from ART-na?ve individuals were defective in their ability to produce intracellular IFN-?. Together, our results suggest that the levels of 2B4 expression and the downstream co-inhibitory signaling events may contribute to impaired iNKT cell responses.
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MAIT cells represent an evolutionarily conserved, MR1-restricted, innate-like cell subset that express high levels of CD161; have a canonical semi-invariant TCR iVα7.2; and may have an important role in mucosal immunity against various bacterial and fungal pathogens. Mature MAIT cells are CD161hiPLZFhiIL-18Rα+iVα7.2+γδ-CD3+CD8+ T cells and occur in the peripheral blood, liver, and mucosa of humans. MAIT cells are activated by a metabolic precursor of riboflavin synthesis presented by MR1 and, therefore, respond to many bacteria and some fungi. Despite their broad antibacterial PROPERTIES, their functional role in persistent viral infections is poorly understood. Although there is an increasing line of evidence portraying the depletion of MAIT cells in HIV disease, the magnitude and the potential mechanisms underlying such depletion remain unclear. Recent studies suggest that MAIT cells are vulnerable to immune exhaustion as a consequence of HIV and hepatitis C virus infections and HIV/tuberculosis coinfections. HIV infection also appears to cause functional depletion of MAIT cells resulting from abnormal expression of T-bet and EOMES, and effective ART is unable to completely salvage functional MAIT cell loss. Depletion and exhaustion of peripheral MAIT cells may affect mucosal immunity and could increase susceptibility to opportunistic infections during HIV infection. Here, we review some of the important mechanisms associated with depletion and functional loss of MAIT cells and also suggest potential immunotherapeutic strategies to restore MAIT cell functions, including the use of IL-7 to restore effector functions in HIV disease.
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In this paper we present cellular senescence as the ultimate driver of the aging process, as a “causal nexus” that bridges microscopic subcellular damage with the phenotypic, macroscopic effect of aging. It is important to understand how the various types of subcellular damage correlated with the aging process lead to the larger, visible effects of anatomical aging. While it has always been assumed that subcellular damage (cause) results in macroscopic aging (effect), the bridging link between the two has been hard to define. Here, we propose that this bridge, which we term the “causal nexus”, is in fact cellular senescence. The subcellular damage itself does not directly cause the visible signs of aging, but rather, as the damage accumulates and reaches a critical mass, cells cease to proliferate and acquire the deleterious “senescence-associated secretory phenotype” (SASP) which then leads to the macroscopic consequences of tissue breakdown to create the physiologically aged phenotype. Thus senescence is a precondition for anatomical aging, and this explains why aging is a gradual process that remains largely invisible during most of its progression. The subcellular damage includes shortening of telomeres, damage to mitochondria, aneuploidy, and DNA double-strand breaks triggered by various genetic, epigenetic, and environmental factors. Damage pathways acting in isolation or in concert converge at the causal nexus of cellular senescence. In each species some types of damage can be more causative than in others and operate at a variable pace; for example, telomere erosion appears to be a primary cause in human cells, whereas activation of tumor suppressor genes is more causative in rodents. Such species-specific mechanisms indicate that despite different initial causes, most of aging is traced to a single convergent causal nexus: senescence. The exception is in some invertebrate species that escape senescence, and in non-dividing cells such as neurons, where senescence still occurs, but results in the SASP rather than loss of proliferation plus SASP. Aging currently remains an inevitable endpoint for most biological organisms, but the field of cellular senescence is primed for a renaissance and as our understanding of aging is refined, strategies capable of decelerating the aging process will emerge.
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Background. Mucosal-associated invariant T (MAIT) cells play an important role in innate host defense. MAIT cells appear to undergo exhaustion, and are functionally weakened in chronic viral infections. However, their role in chronic hepatitis C virus (HCV) infection remains unclear. Materials and methods. We investigated the frequency of CD8+CD161++TCR Vα7.2+ MAIT cells in a cross-sectional cohort of chronic HCV patients (n=25) and healthy controls (n=25). Peripheral blood mononuclear cells were investigated for circulating MAIT cell frequency, liver-homing (CCR5 and CD103), biomarkers of immune exhaustion (PD-1, TIM-3 and CTLA-4), chronic immune activation (CD38 and HLA-DR), and immunosenescence (CD57) by flow cytometry. Results. The frequency of MAIT cells was significantly decreased, and increased signs of immune exhaustion and chronic immune activation were clearly evident on MAIT cells of chronic HCV-infected patients. Decrease of CCR5 on circulating MAIT cells is suggestive of their peripheral loss in chronic HCV infection. MAIT cells also showed significantly increased levels of HLA-DR, CD38, PD-1, TIM-3 and CTLA-4, besides CD57 in the HCV group. Conclusions. Immune exhaustion and senescence of CD8+CD161++TCR Vα7.2+ MAIT cells could contribute to diminished innate defense attributes likely facilitating viral persistence and HCV disease progression.
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The isolation and characterization of 25 strains of human diploid fibroblasts derived from fetuses are described. Routine tissue culture techniques were employed. Other than maintenance of the diploid karyotype, ten other criteria serve to distinguish these strains from heteroploid cell lines. These include retention of sex chromatin, histotypical differentiation, inadaptability to suspended culture, non-malignant characteristics in vivo, finite limit of cultivation, similar virus spectrum to primary tissue, similar cell morphology to primary tissue, increased acid production compared to cell lines, retention of Coxsackie A9 receptor substance, and ease with which strains can be developed. Survival of cell strains at - 70 °C with retention of all characteristics insures an almost unlimited supply of any strain regardless of the fact that they degenerate after about 50 subcultivations and one year in culture. A consideration of the cause of the eventual degeneration of these strains leads to the hypothesis that non-cumulative external factors are excluded and that the phenomenon is attributable to intrinsic factors which are expressed as senescence at the cellular level. With these characteristics and their extremely broad virus spectrum, the use of diploid human cell strains for human virus vaccine production is suggested. In view of these observations a number of terms used by cell culturists are redefined.
Huang et al. 2008. J. Exp. Med. doi:10.1084/jem.20072579 [OpenUrl][1][Abstract/FREE Full Text][2] [1]: {openurl}?query=rft_id%253Dinfo%253Adoi%252F10.1084%252Fjem.20072579%26rft_id%253Dinfo%253Apmid%252F18443227%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%
The ability of antigen-specific T cells to simultaneously produce multiple cytokines is thought to correlate with the functional capacity and efficacy of T cells. These 'polyfunc-tional' T cells have been associated with control of HIV. We aimed to assess the impact of co-infection with Mycobacterium tuberculosis (MTB) on HIV-specific CD8+ and CD4+ T cell function. We assessed T cell functionality in 34 South African adults by investigating the IFN-y, IL-2, TNF-α, IL-21 and IL-17 cytokine secretion capacity, using polychromatic flow cytometry, following HIV Gag-specific stimulation of peripheral blood mononuclear cells. We show that MTB is associated with lower HIV-specific T cell function in co-infected as compared to HIV mono-infected individuals. This decline in function was greatest in co-infection with active Tuberculosis (TB) compared to co-infection with latent MTB (LTBI), suggesting that mycobacterial load may contribute to this loss of function. The described impact of MTB on HIV-specific T cell function may be a mechanism for increased HIV disease progression in co-infected subjects as functionally impaired T cells may be less able to control HIV.