Co-infection with Mycobacterium tuberculosis (MTB) and HIV-1 is a common occurrence in sub-Saharan African Countries. In a significant portion of dual-infected patients initiation of anti-retroviral treatment (ART) results in early onset of clinical and laboratory alterations related to re-acutization of MTB infection, collectively known as Immune Restoration Inflammatory Syndrome (IRIS), the pathogenesis and immune correlates of which are largely unknown at present. We propose to analyze a cohort of HIV-infected individuals developing MTB-related IRIS after ART initiation, by measuring adaptive and innate immune functions. Specifically, we will test the hypotheses that: A- innate immune function, as measured by accessory cell activation (antigen presentation and responsiveness to Toll-like receptors (TLR) 2 7/8 and 9 stimulation) and natural killer cell responses (cytotoxic and cytokine secretion) is directly associated with IRIS and is significantly increased in IRIS patients as compared to non-IRIS HIV-infected controls undergoing ART for comparable periods of time: and B- baseline frequency, activation and function of innate immune effectors may predict a future IRIS outcome in MTB/HIV-1 dual-infected subjects. We will address these hypotheses by comparing the levels of innate and adaptive immune function in whole blood and cryppreserved PBMC from MTB-related IRIS patients and two cohorts of matched non-IRIS, ART-treated controls (asymptomatic or TB co-infected) measuring: A) the frequency of circulating NK subsets, and their IFN-gamma secretion and degranulation responses to interaction with cytokines or target cells. B) the frequency of CD11c myeloid and CD123 plasmacytoid DC, and their cytokine responses to TOLL-like receptor (TLR)-2, 7/8, and 9 binding by specific ligands. C) CD4+ and CD8+ T-cell memory subsets and their proliferative, cytokine and degranulation recall responses to MTB antigens. Completion of this study will provide the first characterization of innate and adaptive correlates to a clinical syndrome that has remained largely unstudied, yet is commonly encountered upon ART initiation in HIV-infected subjects with low CD4 count. Our proposal leverages our unique access to a large cohort (>50 new patients/week) of South African ART-naive patients initiating treatment with CD4 counts under 200 cells/(il, and represents a collaboration between the Wistar Institute (Philadelphia, PA), the """"""""Comprehensive HIV and AIDS Care, Management and Treatment for South Africa"""""""" program at the Clinical HIV Research Unit and the Department of Hematology, University of the Witwatersrand (Johannesburg, ZA) and the University of Massachusetts at Amherst. ? ? ?
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