Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.
Tessera Therapeutics , Somerville, MA, USA.
J Exp Med. 2024 Sep 2;221(9). doi: 10.1084/jem.20240391. Epub 2024 Aug 14.
HIV-1 antiretroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses, leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here, we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000× less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir, thereby influencing cytopathic effects and proviral immune evasion.
HIV-1 抗逆转录病毒疗法非常有效，但无法消除潜伏性前病毒库，因此需要终身治疗。整合到完整潜伏性前病毒库中的整合位点如何影响其自身或邻近基因的表达或储存动力学，目前还知之甚少。在这里，我们报告了从 HIV 感染者直接获得的培养 T 细胞、工程化原代 T 细胞和细胞系中完整潜伏性 HIV-1 整合部位的前病毒和邻近基因转录情况。前病毒基因的表达与静止状态下内源性基因表达水平相关，但与激活状态下无关。值得注意的是，潜伏性前病毒启动子的活性比在产感染细胞中低 100-10000 倍，在静止或激活状态下对邻近基因表达几乎没有或没有可测量的影响。因此，整合位点对潜伏性储库中完整 HIV-1 前病毒的转录活性具有主导作用，从而影响细胞病变效应和前病毒免疫逃逸。
