T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy

Abstract

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal.

Longitudinal study reveals HIV-1–infected CD4+ T cell dynamics during long-term antiretroviral therapy

“…Fewer sequences were obtained per time point from controllers (average 13, range 3-25), consistent with the lower frequency of latently infected cells in these individuals (50)(51)(52). translated to yield viral proteins recognized by cytotoxic T lymphocytes (CTLs) (17,27,28,(33)(34)(35). If this is the case, then depletion of intact and certain defective HIV-1 proviruses should occur over long periods of time in PLWH on suppressive ART, and a cure may eventually be achieved with strategies that accelerate such depletion.…”

“…If drivers of clonal proliferation such as antigen recognition by the host cell also induce HIV-1 gene expression, then cells harboring intact proviruses may be less likely to undergo extensive clonal proliferation than uninfected cells due to cytopathic effects of HIV-1 gene expression or CTL pressure. For defective proviruses, the extent of expansion may depend on the nature of the defect and which viral genes can be expressed (27,28,34). For some defective proviruses, particularly those with very large deletions, induction of viral gene expression is unlikely to lead to viral cytopathic effects or CTL recognition.…”

“…The HIV-1 proviral landscape does not change dramatically over time on ART. Activated CD4 + T cells harboring intact proviruses and certain types of defective proviruses may be subject to negative selection by HIV-1-specific CTLs in people on suppressive ART (17,27,28,34,54,55). If selection operates on cells comprising the latent reservoir, perhaps during transient periods of cellular activation, a decreased proportion of intact proviruses might be observed over time, while proviruses with very large deletions encompassing many ORFs might increase in proportion.…”

Pregnancy Gestation Impacts on HIV-1-Specific Granzyme B Response and Central Memory CD4 T Cells

“…However, IL-10 response to Nef was decreased and direct correlations of Gag and Nef IFNγ, IL-2, IL-10, and granzyme B responses were reversed with pregnancy status, suggesting the maintenance of Gag and Nef-specific T-cell populations is affected by pregnancy. This could be caused by changes in HIV-1-specific T-cell subset stimulation related to changes in the proportion of antigen production suggesting a potential switch from latent to activated HIV-1 reservoir cells (50,51). This antigenic load shift is reminiscent of the changes observed in HIV-1 positive individuals during treatment interruption (52).…”

HIV-specific T-cell responses reflect substantive in vivo interactions with infected cells despite long-term therapy

“…2 and Table 1). We previously assessed HIV-specific T-cell responses in A5321 at study entry, a median of 7 (range 4-15) years after ART initiation (32). Here, we extended these results with batched analysis of samples from 24 and 168 weeks after study entry.…”