J. David Gladstone Institutesgrid.249878.8, San Francisco, California, USA.
Institute for Translational HIV Research, University Hospital Essen, University of Duisburg-Essengrid.5718.b, Essen, Germany.
mBio. 2022 Oct 26;13(5):e0189122. doi: 10.1128/mbio.01891-22. Epub 2022 Sep 8.
HIV infects long-lived CD4 memory T cells, establishing a latent viral reservoir that necessitates lifelong antiretroviral therapy (ART). How this reservoir is formed so quickly after infection remains unclear. We now show the innate inflammatory response to HIV infection results in CCL2 chemokine release, leading to recruitment of cells expressing the CCR2 receptor, including a subset of central memory CD4 T cells. Supporting a role for the CCL2/CCR2 axis in rapid reservoir formation, we find (i) treatment of humanized mice with anti-CCL2 antibodies during early HIV infection decreases reservoir seeding and preserves CCR2/5 cells and (ii) CCR2/5 cells from the blood of HIV-infected individuals on long-term ART contain significantly more integrated provirus than CCR2/5-negative memory or naive cells. Together, these studies support a model where the host's innate inflammatory response to HIV infection, including CCL2 production, leads to the recruitment of CCR2/5 central memory CD4 T cells to zones of virus-associated inflammation, likely contributing to rapid formation of the latent HIV reservoir. There are currently over 35 million people living with HIV worldwide, and we still have no vaccine or scalable cure. One of the difficulties with HIV is its ability to rapidly establish a viral reservoir in lymphoid tissues that allows it to elude antivirals and the immune system. Thus, it is important to understand how HIV accomplishes this so we can develop preventive strategies. Our current results show that an early inflammatory response to HIV infection includes production of the chemokine CCL2, which recruits a unique subset of CCR2/5 CD4 T cells that become infected and form a significant reservoir for latent infection. Furthermore, we show that blockade of CCL2 in humanized mice significantly reduces persistent HIV infection. This information is relevant to the development of therapeutics to prevent and/or treat chronic HIV infections.
HIV 感染寿命长的 CD4 记忆 T 细胞，建立潜伏的病毒储存库，这需要终身抗逆转录病毒治疗（ART）。感染后储存库如此迅速地形成的机制仍不清楚。我们现在表明，HIV 感染的先天炎症反应导致趋化因子 CCL2 的释放，导致表达 CCR2 受体的细胞招募，包括中央记忆 CD4 T 细胞的一个亚群。支持 CCL2/CCR2 轴在快速储存库形成中的作用，我们发现 (i) 在早期 HIV 感染期间用抗 CCL2 抗体治疗人源化小鼠可减少储存库播种并保留 CCR2/5 细胞，和 (ii) 长期接受 ART 的 HIV 感染个体的血液中的 CCR2/5 细胞含有明显更多整合的前病毒比 CCR2/5-阴性记忆或幼稚细胞。总的来说，这些研究支持这样一种模型，即宿主对 HIV 感染的先天炎症反应，包括 CCL2 的产生，导致 CCR2/5 中央记忆 CD4 T 细胞募集到病毒相关炎症区域，可能有助于快速形成潜伏的 HIV 储存库。目前，全世界有超过 3500 万人感染了 HIV，我们仍然没有疫苗或可扩展的治疗方法。HIV 的一个困难之处在于它能够迅速在淋巴组织中建立病毒储存库，使其逃避抗病毒药物和免疫系统。因此，了解 HIV 如何做到这一点非常重要，这样我们就可以开发预防策略。我们目前的结果表明，HIV 感染的早期炎症反应包括趋化因子 CCL2 的产生，该趋化因子招募了一个独特的 CCR2/5 CD4 T 细胞亚群，这些细胞被感染并形成潜伏感染的重要储存库。此外，我们还表明，在人源化小鼠中阻断 CCL2 可显著减少持续性 HIV 感染。这些信息与开发预防和/或治疗慢性 HIV 感染的治疗方法有关。
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