HIV rapidly rebounds after interruption of antiretroviral therapy (ART). HIV-specific CD8+ T cells may act to prevent early events in viral reactivation. However, the presence of viral immune escape mutations may limit the effect of CD8+ T cells on viral rebound. Here, we studied the impact of CD8 immune pressure on post-treatment rebound of barcoded SIVmac293M in 14 Mamu-A*01 positive rhesus macaques that initiated ART on day 14, and subsequently underwent two analytic treatment interruptions (ATIs). Rebound following the first ATI (seven months after ART initiation) was dominated by virus that retained the wild-type sequence at the Mamu-A*01 restricted Tat-SL8 epitope. By the end of the two-month treatment interruption, the replicating virus was predominantly escaped at the Tat-SL8 epitope. Animals reinitiated ART for 3 months prior to a second treatment interruption. Time-to-rebound and viral reactivation rate were significantly slower during the second treatment interruption compared to the first. Tat-SL8 escape mutants dominated early rebound during the second treatment interruption, despite the dominance of wild-type virus in the proviral reservoir. Furthermore, the escape mutations detected early in the second treatment interruption were well predicted by those replicating at the end of the first, indicating that escape mutant virus in the second interruption originated from the latent reservoir as opposed to evolving de novo post rebound. SL8-specific CD8+ T cell levels in blood prior to the second interruption were marginally, but significantly, higher (median 0.73% vs 0.60%, p = 0.016). CD8+ T cell depletion approximately 95 days after the second treatment interruption led to the reappearance of wild-type virus. This work suggests that CD8+ T cells can actively suppress the rebound of wild-type virus, leading to the dominance of escape mutant virus after treatment interruption.

中文翻译：

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通过 CD8+ T 细胞“筛选”潜伏期重新激活的 SIV，优先选择病毒逃逸突变体。

抗逆转录病毒治疗 (ART) 中断后，艾滋病毒迅速反弹。HIV 特异性 CD8+ T 细胞可能起到预防病毒再激活的早期事件的作用。然而，病毒免疫逃逸突变的存在可能会限制 CD8+ T 细胞对病毒反弹的影响。在这里，我们研究了 CD8 免疫压力对 14 只 Mamu-A*01 阳性恒河猴治疗后条形码 SIVmac293M 反弹的影响，这些猕猴在第 14 天开始 ART，随后接受了两次分析治疗中断 (ATI)。第一次 ATI（ART 开始后七个月）后的反弹主要由保留 Mamu-A*01 限制性 Tat-SL8 表位野生型序列的病毒主导。两个月的治疗中断结束时，复制的病毒主要在 Tat-SL8 表位处逃逸。在第二次治疗中断之前，动物重新开始 ART 3 个月。与第一次相比，第二次治疗中断期间的反弹时间和病毒再激活率显着减慢。尽管野生型病毒在原病毒库中占主导地位，但在第二次治疗中断期间，Tat-SL8 逃逸突变体主导了早期反弹。此外，在第二次治疗中断早期检测到的逃逸突变被在第一次治疗中断结束时复制的病毒很好地预测了，这表明第二次治疗中断中的逃逸突变病毒起源于潜伏病毒库，而不是反弹后从头进化。第二次中断之前，血液中 SL8 特异性 CD8+ T 细胞水平略有升高，但显着升高（中位值 0.73% vs 0.60%，p = 0.016）。第二次治疗中断后约 95 天，CD8+ T 细胞耗竭导致野生型病毒再次出现。这项工作表明，CD8+ T 细胞可以主动抑制野生型病毒的反弹，导致治疗中断后逃逸突变病毒占主导地位。