Creighton Rachel L, Hughes Sean M, Hladik Florian, Gornalusse Germán G
Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, WA, United States.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, United States.
Front Immunol. 2025 May 14;16:1589752. doi: 10.3389/fimmu.2025.1589752. eCollection 2025.
The barrier to HIV cure is the HIV reservoir, which is composed of latently infected CD4 T cells and myeloid cells that carry stably integrated and replication-competent provirus. The gastrointestinal tract (GIT) contains a substantial part of the HIV reservoir and its immunophysiology could be especially conducive for HIV persistence and reactivation. However, the exact cellular microenvironment and molecular mechanisms that govern the renewal of provirus-harboring cells and proviral reactivation in the GIT remain unclear. In this review, we outline the evidence supporting an overarching hypothesis that interferon activity driven by specialized enterocytes creates a microenvironment that fosters proliferation of latently infected CD4 T cells and sporadic HIV reactivation from these cells. First, we describe unique immunologic features of the gastrointestinal associated lymphoid tissue (GALT), specifically highlighting IFN activity in specialized enterocytes and potential interactions between these cells and neighboring HIV susceptible cells. Then, we will describe dysregulation of IFN signaling in HIV infection and how IFN dysregulation in the GALT may contribute to the persistence and reactivation of the latent HIV reservoir. Finally, we will speculate on the clinical implications of this hypothesis for HIV cure strategies and outline the next steps.
治愈艾滋病的障碍是艾滋病毒储存库，它由潜伏感染的CD4 T细胞和携带稳定整合且具有复制能力的前病毒的髓样细胞组成。胃肠道（GIT）包含了很大一部分艾滋病毒储存库，其免疫生理学可能特别有利于艾滋病毒的持续存在和重新激活。然而，在胃肠道中控制携带前病毒细胞的更新和前病毒重新激活的确切细胞微环境和分子机制仍不清楚。在这篇综述中，我们概述了支持一个总体假设的证据，即由特殊肠上皮细胞驱动的干扰素活性创造了一个微环境，促进潜伏感染的CD4 T细胞的增殖以及这些细胞中艾滋病毒的散发性重新激活。首先，我们描述胃肠道相关淋巴组织（GALT）的独特免疫学特征，特别强调特殊肠上皮细胞中的干扰素活性以及这些细胞与邻近的艾滋病毒易感细胞之间的潜在相互作用。然后，我们将描述艾滋病毒感染中干扰素信号的失调，以及GALT中的干扰素失调如何可能导致潜伏艾滋病毒储存库的持续存在和重新激活。最后，我们将推测这一假设对艾滋病治愈策略的临床意义，并概述接下来的步骤。
