Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA.
mBio. 2021 Oct 26;12(5):e0244721. doi: 10.1128/mBio.02447-21. Epub 2021 Sep 21.
Future HIV-1 curative therapies require a thorough understanding of the distribution of genetically-intact HIV-1 within T-cell subsets during antiretroviral therapy (ART) and the cellular mechanisms that maintain this reservoir. Therefore, we sequenced near-full-length HIV-1 genomes and identified genetically-intact and genetically-defective genomes from resting naive, stem-cell memory, central memory, transitional memory, effector memory, and terminally-differentiated CD4 T-cells with known cellular half-lives from 11 participants on ART. We find that a higher infection frequency with any HIV-1 genome was significantly associated with a shorter cellular half-life, such as transitional and effector memory cells. A similar enrichment of genetically-intact provirus was observed in these cells with relatively shorter half-lives. We found that effector memory and terminally-differentiated cells also had significantly higher levels of expansions of genetically-identical sequences, while only transitional and effector memory cells contained genetically-intact proviruses that were part of a cluster of identical sequences. Expansions of identical sequences were used to infer cellular proliferation from clonal expansion. Altogether, this indicates that specific cellular mechanisms such as short half-life and proliferative potential contribute to the persistence of genetically-intact HIV-1. The design of future HIV-1 curative therapies requires a more thorough understanding of the distribution of genetically-intact HIV-1 within T-cell subsets as well as the cellular mechanisms that maintain this reservoir. These genetically-intact and presumably replication-competent proviruses make up the latent HIV-1 reservoir. Our investigations into the possible cellular mechanisms maintaining the HIV-1 reservoir in different T-cell subsets have revealed a link between the half-lives of T-cells and the level of proviruses they contain. Taken together, we believe our study shows that more differentiated and proliferative cells, such as transitional and effector memory T-cells, contain the highest levels of genetically-intact proviruses, and the rapid turnover rate of these cells contributes to the expansion of genetically-intact proviruses within them. Therefore, our study delivers an in-depth assessment of the cellular mechanisms, such as cellular proliferation and half-life, that contribute to and maintain the latent HIV-1 reservoir.
未来的 HIV-1 治愈疗法需要深入了解在抗逆转录病毒治疗 (ART) 期间，遗传完整的 HIV-1 在 T 细胞亚群中的分布情况，以及维持这种储库的细胞机制。因此，我们对接近全长的 HIV-1 基因组进行了测序，并从接受 ART 的 11 名参与者的静止性幼稚、干细胞记忆、中央记忆、过渡记忆、效应记忆和终末分化 CD4 T 细胞中鉴定了遗传完整和遗传缺陷的基因组，这些细胞的细胞半衰期已知。我们发现，任何 HIV-1 基因组的更高感染频率与较短的细胞半衰期显著相关，如过渡性和效应记忆细胞。在这些半衰期相对较短的细胞中，也观察到了遗传完整前病毒的类似富集。我们发现，效应记忆和终末分化细胞还具有显著更高水平的遗传相同序列的扩增，而只有过渡性和效应记忆细胞含有遗传完整的前病毒，这些前病毒是相同序列簇的一部分。相同序列的扩增用于从克隆扩增推断细胞增殖。总之，这表明特定的细胞机制，如半衰期短和增殖潜力，有助于遗传完整的 HIV-1 的持续存在。未来的 HIV-1 治愈疗法的设计需要更深入地了解遗传完整的 HIV-1 在 T 细胞亚群中的分布情况，以及维持这种储库的细胞机制。这些遗传完整的、推测具有复制能力的前病毒构成了潜伏的 HIV-1 储库。我们对不同 T 细胞亚群中维持 HIV-1 储库的可能细胞机制的研究表明，T 细胞的半衰期与它们所包含的前病毒水平之间存在联系。总的来说，我们认为我们的研究表明，更分化和增殖的细胞，如过渡性和效应记忆 T 细胞，含有最高水平的遗传完整前病毒，这些细胞的快速周转率导致它们内部遗传完整前病毒的扩增。因此，我们的研究深入评估了细胞机制，如细胞增殖和半衰期，这些机制有助于并维持潜伏的 HIV-1 储库。
