Infectious Disease Division, Brigham Women's Hospital, Boston.
The Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
Curr Opin HIV AIDS. 2024 May 1;19(3):110-115. doi: 10.1097/COH.0000000000000845. Epub 2024 Feb 28.
Elite controllers (ECs) and Posttreatment controllers (PTCs) represent a small subset of individuals who are capable of maintaining drug-free control of HIV plasma viral loads despite the persistence of a replication-competent viral reservoir. This review aims to curate recent experimental studies evaluating viral reservoirs that distinguish EC/PTC and may contribute to their ability to maintain undetectable viral loads in the absence of antiretroviral therapy.
Recent studies on ECs have demonstrated that integration sites of intact proviruses in EC/PTC are markedly biased towards heterochromatin regions; in contrast, intact proviruses in accessible and permissive chromatin were profoundly underrepresented. Of note, no such biases were noted when CD4 + T cells from EC were infected directly ex vivo, suggesting that the viral reservoir profile in EC is not related to altered integration site preferences during acute infection, but instead represents the result of immune-mediated selection mechanisms that can eliminate proviruses in transcriptionally-active euchromatin regions while promoting preferential persistence of intact proviruses in nonpermissive genome regions. Proviral transcription in such "blocked and locked" regions may be restricted through epigenetic mechanisms, protecting them from immune-recognition but presumably limiting their ability to drive viral rebound. While the exact immune mechanisms driving this selection process remain undefined, recent single-cell analytic approaches support the hypothesis that HIV reservoir cells are subject to immune selection pressure by host factors.
A "blocked and locked" viral reservoir profile may constitute a structural virological correlate of a functional cure of HIV-1 infection. Further research into the immunological mechanism promoting HIV-1 reservoir selection and evolution in EC/PTC is warranted and could inform foreseeable cure strategies.
精英控制者（EC）和治疗后控制者（PTC）是一小部分能够在持续存在复制能力病毒库的情况下，无需抗逆转录病毒治疗即可实现 HIV 血浆病毒载量无药物控制的人群。本综述旨在收集最近评估能够区分 EC/PTC 的病毒库的实验研究，这些研究可能有助于解释他们能够在没有抗逆转录病毒治疗的情况下维持无法检测到的病毒载量的原因。
最近对 EC 的研究表明，EC/PTC 中完整前病毒的整合位点明显偏向异染色质区域；相比之下，在可及和允许的染色质中，完整的前病毒则严重代表性不足。值得注意的是，当直接从 EC 中分离的 CD4 + T 细胞进行体外感染时，并未观察到这种偏向，这表明 EC 中的病毒库特征与急性感染期间改变的整合位点偏好无关，而是代表了免疫介导的选择机制的结果，这些机制可以消除转录活跃的常染色质区域中的前病毒，同时促进非允许基因组区域中完整前病毒的优先持续存在。这种“阻断和锁定”区域中的前病毒转录可能受到表观遗传机制的限制，从而保护它们免受免疫识别，但可能限制它们驱动病毒反弹的能力。虽然驱动这种选择过程的确切免疫机制尚不清楚，但最近的单细胞分析方法支持这样一种假设，即 HIV 储库细胞受到宿主因素的免疫选择压力。
“阻断和锁定”的病毒库特征可能构成 HIV-1 感染功能性治愈的结构病毒学相关因素。进一步研究促进 EC/PTC 中 HIV-1 储库选择和进化的免疫机制是必要的，并且可以为可预见的治疗策略提供信息。
