Division of Experimental Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital, University of California, San Francisco, CA 94110, USA.
Division of Gastroenterology, Department of Medicine, Zuckerberg San Francisco General Hospital, University of California, San Francisco, CA 94110, USA.
Viruses. 2019 Mar 13;11(3):256. doi: 10.3390/v11030256.
Although antiretroviral therapy (ART) greatly suppresses HIV replication, lymphoid tissues remain a sanctuary site where the virus may replicate. Tracking the earliest steps of HIV spread from these cellular reservoirs after drug cessation is pivotal for elucidating how infection can be prevented. In this study, we developed an in vivo model of HIV persistence in which viral replication in the lymphoid compartments of humanized mice was inhibited by the HIV reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) to very low levels, which recapitulated ART-suppression in HIV-infected individuals. Using a combination of RNAscope in situ hybridization (ISH) and immunohistochemistry (IHC), we quantitatively investigated the distribution of HIV in the lymphoid tissues of humanized mice during active infection, EFdA suppression, and after drug cessation. The lymphoid compartments of EFdA-suppressed humanized mice harbored very rare transcription/translation-competent HIV reservoirs that enable viral rebound. Our data provided the visualization and direct measurement of the early steps of HIV reservoir expansion within anatomically intact lymphoid tissues soon after EFdA cessation and suggest a strategy to enhance therapeutic approaches aimed at eliminating the HIV reservoir.
尽管抗逆转录病毒疗法（ART）能极大地抑制 HIV 复制，但淋巴组织仍然是病毒可能复制的避难所。追踪药物停止后病毒从这些细胞储库中最初的扩散步骤，对于阐明如何预防感染至关重要。在本研究中，我们开发了一种 HIV 持续存在的体内模型，其中 HIV 逆转录酶抑制剂 4'-乙炔基-2-氟-2'-脱氧腺苷（EFdA）将人源化小鼠淋巴组织中的病毒复制抑制到非常低的水平，这再现了 HIV 感染者接受 ART 抑制的情况。我们使用 RNAscope 原位杂交（ISH）和免疫组织化学（IHC）的组合，定量研究了 HIV 在人源化小鼠活跃感染、EFdA 抑制和药物停止后的淋巴组织中的分布。EFdA 抑制的人源化小鼠的淋巴组织中存在极少数能进行转录/翻译的、有功能的 HIV 储库，使病毒得以反弹。我们的数据提供了 HIV 储库在 EFdA 停止后不久在解剖上完整的淋巴组织内扩张的早期步骤的可视化和直接测量，并提出了一种增强旨在消除 HIV 储库的治疗方法的策略。
