Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington DC, USA.
Ragon Institute of Massachusetts Institute of Technology (MIT), Massachusetts General Hospital (MGH), and Harvard University, Cambridge, Massachusetts, USA.
J Clin Invest. 2018 Feb 1;128(2):876-889. doi: 10.1172/JCI97555. Epub 2018 Jan 22.
The presence of persistent, latent HIV reservoirs in CD4+ T cells obstructs current efforts to cure infection. The so-called kick-and-kill paradigm proposes to purge these reservoirs by combining latency-reversing agents with immune effectors such as cytotoxic T lymphocytes. Support for this approach is largely based on success in latency models, which do not fully reflect the makeup of latent reservoirs in individuals on long-term antiretroviral therapy (ART). Recent studies have shown that CD8+ T cells have the potential to recognize defective proviruses, which comprise the vast majority of all infected cells, and that the proviral landscape can be shaped over time due to in vivo clonal expansion of infected CD4+ T cells. Here, we have shown that treating CD4+ T cells from ART-treated individuals with combinations of potent latency-reversing agents and autologous CD8+ T cells consistently reduced cell-associated HIV DNA, but failed to deplete replication-competent virus. These CD8+ T cells recognized and potently eliminated CD4+ T cells that were newly infected with autologous reservoir virus, ruling out a role for both immune escape and CD8+ T cell dysfunction. Thus, our results suggest that cells harboring replication-competent HIV possess an inherent resistance to CD8+ T cells that may need to be addressed to cure infection.
潜伏的 HIV 储库持续存在于 CD4+T 细胞中，这阻碍了目前治愈感染的努力。所谓的“踢除与杀伤”范式，通过将潜伏期逆转剂与细胞毒性 T 淋巴细胞等免疫效应细胞结合起来，以清除这些储库。这种方法的支持主要基于潜伏期模型的成功，这些模型不能完全反映长期接受抗逆转录病毒疗法（ART）的个体中潜伏储库的组成。最近的研究表明，CD8+T 细胞有可能识别包含绝大多数受感染细胞的缺陷前病毒，并且由于受感染的 CD4+T 细胞在体内的克隆扩增，前病毒景观可能会随着时间的推移而改变。在这里，我们已经表明，用有效的潜伏期逆转剂组合和自体 CD8+T 细胞治疗接受 ART 治疗的个体的 CD4+T 细胞，可一致降低细胞相关 HIV DNA，但未能耗尽复制型病毒。这些 CD8+T 细胞识别并有效消除了新感染自体储库病毒的 CD4+T 细胞，排除了免疫逃逸和 CD8+T 细胞功能障碍的作用。因此，我们的研究结果表明，携带复制型 HIV 的细胞对 CD8+T 细胞具有固有抗性，这可能需要加以解决以治愈感染。
