Laboratory of Molecular Immunology, The Rockefeller University, New York, NY.
Howard Hughes Medical Institute, Chevy Chase, MD.
J Exp Med. 2021 Dec 6;218(12). doi: 10.1084/jem.20211427. Epub 2021 Oct 12.
Latent intact HIV-1 proviruses persist in a small subset of long-lived CD4+ T cells that can undergo clonal expansion in vivo. Expanded clones of CD4+ T cells dominate latent reservoirs in individuals on long-term antiretroviral therapy (ART) and represent a major barrier to HIV-1 cure. To determine how integration landscape might contribute to latency, we analyzed integration sites of near full length HIV-1 genomes from individuals on long-term ART, focusing on individuals whose reservoirs are highly clonal. We find that intact proviruses in expanded CD4+ T cell clones are preferentially integrated within Krüppel-associated box (KRAB) domain-containing zinc finger (ZNF) genes. ZNF genes are associated with heterochromatin in memory CD4+ T cells; nevertheless, they are expressed in these cells under steady-state conditions. In contrast to genes carrying unique integrations, ZNF genes carrying clonal intact integrations are down-regulated upon cellular activation. Together, the data suggest selected genomic sites, including ZNF genes, can be especially permissive for maintaining HIV-1 latency during memory CD4+ T cell expansion.
潜伏的完整 HIV-1 前病毒存在于一小部分寿命长的 CD4+T 细胞中，这些细胞可以在体内进行克隆扩增。在长期接受抗逆转录病毒治疗（ART）的个体中，CD4+T 细胞的扩增克隆主导着潜伏库，这是 HIV-1 治愈的主要障碍。为了确定整合景观如何有助于潜伏，我们分析了长期接受 ART 的个体中接近全长 HIV-1 基因组的整合位点，重点关注那些潜伏库高度克隆的个体。我们发现，在扩增的 CD4+T 细胞克隆中，完整的前病毒优先整合在含有 Krüppel 相关盒（KRAB）结构域的锌指（ZNF）基因内。ZNF 基因与记忆 CD4+T 细胞中的异染色质有关；然而，在这些细胞的稳态条件下也表达。与携带独特整合的基因相反，携带克隆完整整合的 ZNF 基因在细胞激活时下调。总之，这些数据表明，包括 ZNF 基因在内的某些基因组位点在记忆 CD4+T 细胞扩增期间可以特别有利于维持 HIV-1 的潜伏。
