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.

HIV特异的CD8 ⁺ T细胞反应可限制未经治疗的感染中的病毒复制。在开始抗逆转录病毒治疗（ART）后，这些反应会减弱，通常认为残留的感染细胞对T细胞是看不见的。我们假设，由于低水平或偶发性蛋白表达，HIV抗原识别可能会在接受ART治疗的个体中持续存在。我们假设，如果持续识别发生，则与早期的HIV基因产物Nef，Tat和Rev相比，优先选择具有更高表达障碍的晚期基因产物，例如Gag，Pol和Env。使用潜伏期的主要细胞模型，我们观察到Nef特异性CD8 ⁺T细胞克隆在重新激活之前表现出对受感染细胞的低水平识别，在此之后不久就表现出强大的识别能力。特定于Gag的CD8 ⁺在这些条件下，T细胞克隆无法识别感染的细胞，这与缺乏可检测的Gag表达有关。我们测量了96名在ART中被抑制7年的个体的HIV特异性T细胞反应，并观察到细胞相关的HIV DNA水平与产生IFN-γ的Nef / Tat的大小之间存在显着的直接相关性。 / Rev特异的T细胞反应。在一个独立的队列中证实了这种相关性（n = 18）。没有检测到艾滋病毒持久性与T细胞对其他艾滋病毒抗原的反应之间的相关性。与Nef / Tat / Rev特异性T细胞的相关性归因于Nef特异性应答，其广度也与HIV DNA水平相关。这些结果表明，在接受ART治疗的个体中持续进行的Nef表达可驱动优先维持和/或扩展对该蛋白质具有反应性的T细胞，这意味着免疫系统可感测感染的细胞。然而，直接的相关性表明识别并不能有效消除被感染的细胞。这些结果增加了即使在没有治疗潜伏期逆转的情况下，增强Nef特异性T细胞的细胞溶解活性也可能导致感染细胞频率降低的可能性。