Many HIV cure strategies propose to elicit HIV-specific CD8+ T cell responses to control and/or eradicate the virus, but they will not be effective if they do not prevent or reverse CD8+ T cell exhaustion. A loss in proliferative capacity is a key feature of exhaustion, but little is known about how this capacity is regulated in these cells. The purpose of this study was to explore the connection between TCF-1, a Wnt-signaling transcription factor, and proliferative capacity in HIV-specific CD8+ T cells.
Cryopreserved PBMCs were sampled from Viremic (VL>8,000 copies/mL; n=14), ART-suppressed (VL<40 copies/mL on stable ART for a median of 2 years; n=10), and Controller (VL<40 copies/mL not on ART; n=12) HIV-infected individuals. Using flow cytometry, HIV-specific CD8+ T cells were identified by staining with Gag, Pol, or Nef-specific MHC Class I (HLA-A*02, *03, *24, or -B*07)-restricted tetramers. Tetramer+ cells were characterized for the expression of transcription factors (TCF-1, Tbet), effector molecules (Granzyme B, Perforin), and surface proteins (PD-1, CD127, CCR7). Proliferation of the tetramer+ population was measured after 6-day in vitro peptide stimulation of CellTraceViolet (CTV)-labeled cells.
HIV-specific tetramer+ CD8+ T cells from Controllers compared to Viremic individuals had greater proliferative responses (%CTVlo 89% vs. 16%; p=0.05; measured in a subset of individuals), were more likely to express CD127 (26% vs. 7%; p=0.0001), and were less likely to express PD-1 (60% vs. 95%; p<0.0001). Median TCF-1 expression was highest in tetramer+ cells from Controllers, followed by ART-suppressed and then Viremic individuals (62% vs. 51% vs. 35%; p<0.0001). TCF-1 expression in these cells was associated with higher CCR7 and CD127, and lower PD-1, Granzyme B, and Tbet expression. Strikingly, expression of TCF-1 (but not PD-1) strongly correlated with proliferative capacity amongst Viremic and Controller individuals (r=0.83, p=0.0008), and was inversely correlated with HIV VL in Viremic individuals (r=-0.85, p=0.02).
TCF-1 expression marks subpopulations of less terminally differentiated tetramer+ HIV-specific CD8+ T cells whose abundance correlates with enhanced proliferative capacity. Whether preservation of TCF-1+ cells is required to prevent HIV-specific T cell exhaustion remains to be investigated, but these data provide a rationale for future studies to evaluate TCF-1 as a target to enhance the efficacy of CD8+ T cell-based HIV cure strategies.