CROI 2016 Abstract eBook
300LB Only T-Cell Responses to Nef/Tat/Rev CorrelateWith Infected Cell Frequencies on ART AllisonThomas 1 ; JohnW. Mellors 2 ; Rajesh Gandhi 3 ; Deborah McMahon 2 ; Joseph J. Eron 4 ; Ronald Bosch 5 ; Christina Lalama 6 ; Joshua Cytkor 2 ; Bruce D.Walker 7 ; Brad Jones 1 1 George Washington Univ, Washington, DC, USA; 2 Univ of Pittsburgh, Pittsburgh, PA, USA; 3 Massachusetts General Hosp, Boston, MA, USA; 4 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5 Harvard Univ, Boston, MA, USA; 6 Harvard Sch of PH, Boston, MA, USA; 7 Ragon Inst of MGH, MIT, and Harvard, Cambridge, MA, USA Background: HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After initiation of antiretroviral therapy (ART), these responses decay, and the viral reservoir that persists is commonly considered to be invisible to CD8+ T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals, due to low-level or episodic protein expression. We reasoned that the ‘early’ HIV gene products Nef, Tat, and Rev would have lower barriers to expression than the Rev-dependent late gene products. Ongoing recognition of HIV antigens in ART-treated individuals could manifest as associations between T-cell responses and either numbers of infected cells (cell associated HIV DNA), or residual HIV RNA expression (cell-associated or cell-free). Methods: We performed IFN-gamma ELISPOT assays with peptide pools spanning: i) Gag ii) Env iii) Pol iv) Nef,Tat,Rev v) Vif,Vpr,Vpu vi) CMV-pp65 in cross-section on PBMC from a cohort of 99 individuals suppressed on ART (<50cp/mL HIV RNA), for a median of 6.8 years (ACTG HIV Reservoirs Cohort Study, A5321). Cell associated HIV DNA and RNA, and plasma HIV RNA were measured by qPCR. Results: HIV-specific T-cell responses were primarily directed against Gag, Pol, and Nef/Tat/Rev with mean±SD values of 171±271, 295±282, and 124±205 SFU/10 6 cells, respectively. We observed a modest but significant correlation between the magnitude of the Nef/Tat/Rev-specific T-cell response and cell-associated HIV DNA (Spearman p=0.026, r=0.23). No correlations were observed between T-cell responses to other HIV antigens and HIV DNA. Nef/Tat/Rev-specific T-cell responses did not correlate with pre-ART plasma HIV RNA or CD4 counts. T-cell responses to HIV antigens did not correlate with cell-associated or plasma HIV RNA. Conclusions: These results suggest that ongoing Nef, Tat, and/or Rev expression in ART-treated individuals drives preferential maintenance of T-cells reactive to these proteins. We did not observe evidence for interactions between T-cells targeting other HIV gene products and the viral reservoir. The direct correlation between Nef/Tat/Rev-specific T-cell responses and proviral DNA levels suggests that ongoing recognition of infected cells by these T-cells may occur in ART-treated individuals, but that this does not result in efficient elimination. Strategies to enhance the functionality of Nef/Tat-Rev-specific T-cell responses may facilitate reductions in the reservoir even without the addition of latency reversing agents.
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