Alireza, Saeidi (2017) Studies on immune exhaustion and senescence of certain CD8+ T-CELL phenotypes in HIV-TB co-infected individuals / Alireza Saeidi. PhD thesis, University of Malaya.
Abstract
The syndemic relationship between human immunodeficiency virus (HIV) and tuberculosis (TB) has inflicted a significant disease burden worldwide. Mycobacterium tuberculosis (MTB) and HIV appear to impact the pathogenesis of each other leading to eventual and rapid immune deterioration, the key feature of acquired immunodeficiency syndrome (AIDS). Hence, in depth investigations are required for the improved understanding of the complex interaction between the two pathogens. Several hypotheses have been proposed on the exacerbation of TB by HIV and vice versa. We hypothesized immunosenescence, chronic immune activation and immune exhaustion as potential mechanisms that inflict deterioration of T-cell responses in HIV-TB co-infection. Our investigations showed that increased plasma viremia and decreased CD4:CD8 T-cell ratio observed in HIV-TB co-infected subjects were significantly associated with CD57 levels and markers consistent to late-senescence of CD8+ T cells. Up-regulation of CD57 was associated with loss of CD27 and CD28 on CD8+ T cells, besides the diminished expression of IL-7Rα, CD27 and CD28 levels on CD57+CD4+ T cells. We also observed increase of CD38 on CD8+ T cells. Increased HIV viremia, decreased T-cell counts and CD4:CD8 T-cell ratio were directly associated with elevated levels of CD38 on T cells. Functional deterioration of antigen-specific CD8+ T cells was also clearly evident as intracellular perforin, granzyme B and IFN-γ levels were relatively decreased in HIV-TB co-infected subjects. Given that HIV-TB co-infection results in proliferative senescence, chronic immune activation, and functional insufficiency of CD8+ T cells, we also studied the role of a special subset of CD8+ T cells called TCR Vα7.2+CD161++CD8+ mucosal-associated invariant T (MAIT) cells among anti-retroviral therapy (ART)/anti-TB therapy (ATT) treatment-naïve HIV-TB co-infected, ART/ATT-treated HIV-TB co-infected, ART naïve HIV-infected, ART-treated HIV-infected patients, and HIV negative healthy controls (HCs). Our data revealed that the frequency of MAIT cells was severely depleted iv in HIV-infected as well as HIV-TB co-infected patients. Further, PD-1 expression on MAIT cells was significantly increased in HIV-infected and HIV-TB co-infected patients. The frequency of MAIT cells did not show any significant increase despite the initiation of ART and/or ATT. Majority of the MAIT cells in HCs showed a significant increase in CCR6 expression as compared to HIV-TB co-infection. No marked difference was seen with the expression of CCR5 and CD103 among the study groups. Decrease of CCR6 expression appears to explain why HIV-infected patients display weakened mucosal immune responses. Functional longitudinal investigations on MAIT cells and the signaling events underlying the up-regulation of co-inhibitory molecules using blocking experiments may be required to develop novel intervention strategies to harness protective immune responses in HIV-TB co-infected individuals.
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