Integration features of intact latent HIV-1 in CD4+ T cell clones contribute to viral persistence.
Integration features of intact latent HIV-1 in CD4+ T cell clones contribute to viral persistence.
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DOI：
10.1084/jem.20211427
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发表时间：
2021-12-06
期刊：
影响因子：
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通讯作者：
Cohn LB
中科院分区：
文献类型：
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作者：
Huang AS;Ramos V;Oliveira TY;Gaebler C;Jankovic M;Nussenzweig MC;Cohn LB
这项研究结合了 HIV-1 序列分析和整合位点发现，表明在扩展的潜伏克隆中，ZNF 基因的整合占优势。与其他整合靶标不同，ZNF 基因在 T 细胞激活时下调，这可能有助于潜伏期的维持。潜伏的完整 HIV-1 前病毒持续存在于一小部分长寿命 CD4+ T 细胞中，这些细胞可以在体内进行克隆扩增。 CD4+ T 细胞的扩增克隆在接受长期抗逆转录病毒治疗 (ART) 的个体中占主导地位，是 HIV-1 治愈的主要障碍。为了确定整合景观如何影响潜伏期，我们分析了长期 ART 个体的近全长 HIV-1 基因组的整合位点，重点关注储存库高度克隆的个体。我们发现扩展的 CD4+ T 细胞克隆中的完整原病毒优先整合到包含 Krüppel 相关框 (KRAB) 结构域的锌指 (ZNF) 基因中。 ZNF 基因与记忆 CD4+ T 细胞中的异染色质相关；然而，它们在稳态条件下在这些细胞中表达。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，数据表明，包括 ZNF 基因在内的选定基因组位点特别适合在记忆 CD4+ T 细胞扩增过程中维持 HIV-1 潜伏期。
This study combines HIV-1 sequence analysis and integration site discovery to show a preponderance of integrations into ZNF genes in expanded latent clones. ZNF genes, unlike other integration targets, are downregulated upon T cell activation, which may facilitate latency maintenance. 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.