Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
J Virol. 2019 Apr 3;93(8). doi: 10.1128/JVI.01920-18. Print 2019 Apr 15.
The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4 T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4 T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia. HIV-1 persists as a latent infection in CD4 T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4 T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination.
淋巴组织在抗逆转录病毒治疗 (ART) 中断后 HIV-1 反弹的潜在来源的作用尚不确定。为了解决这个问题，我们比较了从外周血和淋巴结 CD4 T 细胞中获得的潜伏病毒与治疗中断期间出现的病毒。潜伏病毒通过测序近全长 (NFL) 前病毒 DNA 和病毒生长测定 (VOA) 来表征。对 5 名接受 ART 的 HIV-1 感染者进行了研究，其中 4 名参加了 TLR9 激动剂的临床试验，其中包括分析性治疗中断。我们发现，98%的完整或复制有效的克隆序列在血液和淋巴结之间重叠。相比之下，在 4 名接受治疗中断的个体中，没有重叠的 205 个潜伏储库和 125 个反弹序列。然而，反弹病毒可以通过重组来解释。数据表明，在接受 ART 的个体中，携带潜伏病毒的 CD4 T 细胞在血液和淋巴组织之间循环，并支持重组可能在反弹病毒血症的出现中发挥作用的观点。HIV-1 在 CD4 T 细胞中以潜伏感染的形式持续存在，在接受 ART 的感染者的淋巴组织中可以发现这种感染。然而，这个组织储库的重要性及其对 ART 中断后病毒反弹的贡献尚不清楚。在这项研究中，我们试图比较来自 5 名 HIV-1 感染者血液和淋巴结 CD4 T 细胞的潜伏 HIV-1。此外，我们分析了淋巴结病毒对病毒反弹的贡献。我们观察到，血液和淋巴结中的完整前病毒频率相同。此外，在血液和淋巴结中发现了携带相同前病毒的 T 细胞克隆扩增。这些潜伏储库序列似乎不是反弹病毒的直接来源。相反，潜伏前病毒通过重组对反弹库有贡献。
