Background
Post-treatment controllers (PTCs) of HIV control viremia to low or undetectable levels following discontinuation of ART. Previous studies have suggested a lack of association between ex vivo HIV-specific CD8+ T cell responses and post-treatment control. Here we extended beyond ex vivo evaluations to assess the proliferative capacity of HIV-specific CD8+ T cell responses in PTCs and the immune phenotypes of these responses.
Methods
We evaluated HIV-specific CD8+ T cell responses of 6 PTCs, in comparison to 6 previously ART-treated spontaneous controllers (TCs) and 11 non-controllers (NCs), both pre- and post-treatment interruption (TI). Both PTC and TC were defined as having plasma viral loads <10,000 copies/mL for at least 52 weeks post-TI, with TC additionally having a viral load <10,000 copies/mL at the time of ART initiation. PBMC from each participant were stimulated with overlapping peptide pools to the HIV proteins Gag, Pol, Nef, and Env in two stimulation conditions – a short 6-hour stimulation to identify ex vivo reactive T cells (pre-expansion) and a similar 6-hour restimulation following a 6-day stimulation to identify expanded antigen-specific cells. Samples were analyzed by surface/intracellular cytokine staining and flow cytometry. HIV-specific CD8+ T cells were identified as those double-positive for interferon (IFN)-γ and CD107a.
Results
As with prior studies, there was no significant difference in the frequency of ex vivo pre-expansion HIV-specific CD8+ T cells between the three groups post-TI. However, evaluation of proliferative capacity revealed a significant and marked fold-expansion of HIV-specific cells in PTC following 6-day peptide stimulation compared to NC (P<0.01). Phenotypic analysis of pre-expansion HIV-specific CD8+ T cells revealed that PTC had a significantly higher proportion expressing the stem-like memory markers TCF1 and CD127 than NC (P<0.05). Conversely, HIV-specific CD8+ T cells from NC had higher expression of TOX as well as the inhibitory receptor PD-1 (P<0.01 and P<0.05). Notably, NC also displayed this exhausted HIV-specific CD8+ T cell phenotype pre-TI while ART-suppressed.
Conclusions
HIV-specific CD8+ T cells from PTC demonstrated enhanced proliferative capacity and exhibited a stem-like memory phenotype, whereas NC had responses characterized by immune exhaustion. These findings establish key correlates of post-treatment control which can be leveraged as biomarkers to evaluate therapeutic vaccines and immunotherapies for HIV cure.
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