Human immunodeficiency virus (HIV) persists indefinitely in individuals with HIV who receive antiretroviral therapy (ART) owing to a reservoir of latently infected cells that contain replication-competent virus^1,2,3,4. Here, to better understand the mechanisms responsible for latency persistence and reversal, we used the interleukin-15 superagonist N-803 in conjunction with the depletion of CD8⁺ lymphocytes in ART-treated macaques infected with simian immunodeficiency virus (SIV). Although N-803 alone did not reactivate virus production, its administration after the depletion of CD8⁺ lymphocytes in conjunction with ART treatment induced robust and persistent reactivation of the virus in vivo. We found viraemia of more than 60 copies per ml in all macaques (n = 14; 100%) and in 41 out of a total of 56 samples (73.2%) that were collected each week after N-803 administration. Notably, concordant results were obtained in ART-treated HIV-infected humanized mice. In addition, we observed that co-culture with CD8⁺ T cells blocked the in vitro latency-reversing effect of N-803 on primary human CD4⁺ T cells that were latently infected with HIV. These results advance our understanding of the mechanisms responsible for latency reversal and lentivirus reactivation during ART-suppressed infection.

由于潜伏感染细胞含有具有复制能力的病毒，人类免疫缺陷病毒 (HIV) 在接受抗逆转录病毒治疗 (ART) 的 HIV 感染者体内无限期存留^1,2,3,4 。在这里，为了更好地了解潜伏期持续和逆转的机制，我们使用白细胞介素 15 超级激动剂 N-803 与感染猿免疫缺陷病毒 (SIV) 的 ART 治疗猕猴中 CD8 ⁺淋巴细胞的耗竭相结合。尽管单独使用 N-803 并不能重新激活病毒产生，但在 CD8 ⁺淋巴细胞耗尽后联合 ART 治疗进行给药，可在体内诱导病毒的强烈且持久的重新激活。我们发现所有猕猴（ n = 14；100%）以及 N-803 给药后每周收集的 56 个样本中的 41 个样本（73.2%）的病毒血症超过 60 拷贝/毫升。值得注意的是，在接受 ART 治疗的感染 HIV 的人源化小鼠中获得了一致的结果。此外，我们观察到与 CD8 ⁺ T 细胞共培养阻断了 N-803 对潜伏感染 HIV 的原代人类 CD4 ⁺ T 细胞的体外潜伏期逆转作用。这些结果增进了我们对 ART 抑制感染期间潜伏期逆转和慢病毒重新激活机制的理解。