The latent reservoir of HIV-1 in resting CD4+ T cells is a major barrier to cure. It is unclear whether the latent reservoir resides principally in particular subsets of CD4+ T cells, a finding that would have implications for understanding its stability and developing curative therapies. Recent work has shown that proliferation of HIV-1-infected CD4+ T cells is a major factor in the generation and persistence of the latent reservoir and that latently infected T cells that have clonally expanded in vivo can proliferate in vitro without producing virions. In certain CD4+ memory T cell subsets, the provirus may be in a deeper state of latency, allowing the cell to proliferate without producing viral proteins, thus permitting escape from immune clearance. To evaluate this possibility, we used a multiple stimulation viral outgrowth assay to culture resting naïve, central memory (TCM), transitional memory (TTM), and effector memory (TEM) CD4+ T cells from 10 HIV-1-infected individuals on antiretroviral therapy. On average, only 1.7% of intact proviruses across all T cell subsets were induced to transcribe viral genes and release replication-competent virus after stimulation of the cells. We found no consistent enrichment of intact or inducible proviruses in any T cell subset. Furthermore, we observed notable plasticity among the canonical memory T cell subsets after activation in vitro and saw substantial person-to-person variability in the inducibility of infectious virus release. This finding complicates the vision for a targeted approach for HIV-1 cure based on T cell memory subsets.

中文翻译：

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不同的人类静息记忆 CD4+ T 细胞亚群表现出类似的潜伏 HIV-1 原病毒的低诱导能力。


静息 CD4+ T 细胞中的 HIV-1 潜伏库是治愈的主要障碍。目前尚不清楚潜在储存库是否主要存在于特定的 CD4+ T 细胞亚群中，这一发现对于了解其稳定性和开发治疗方法具有重要意义。最近的研究表明，HIV-1感染的CD4+ T细胞的增殖是潜伏病毒库产生和持续存在的主要因素，并且体内克隆扩增的潜伏感染T细胞可以在体外增殖而不产生病毒粒子。在某些 CD4+ 记忆 T 细胞亚群中，原病毒可能处于更深的潜伏状态，使细胞能够增殖而不产生病毒蛋白，从而逃避免疫清除。为了评估这种可能性，我们使用多重刺激病毒生长测定来培养来自 10 名接受抗逆转录病毒治疗的 HIV-1 感染者的静息初始、中央记忆 (TCM)、过渡记忆 (TTM) 和效应记忆 (TEM) CD4+ T 细胞。平均而言，所有 T 细胞亚群中只有 1.7% 的完整原病毒在刺激细胞后被诱导转录病毒基因并释放具有复制能力的病毒。我们发现任何 T 细胞亚群中都没有一致富集完整或可诱导的原病毒。此外，我们观察到体外激活后典型记忆 T 细胞亚群具有显着的可塑性，并且在感染性病毒释放的诱导性方面发现了显着的人与人差异。这一发现使基于 T 细胞记忆子集的 HIV-1 靶向治疗方法的愿景变得更加复杂。