MINI REVIEW article
Front. Immunol.
Sec. Viral Immunology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1589752
This article is part of the Research TopicHIV and the Gut: Novel Insights into HIV Pathogenesis, Clinical Implications and Therapeutic ApproachesView all articles
The intestinal interferon system and specialized enterocytes as putative drivers of HIV latency
Provisionally accepted
- 1Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington, United States
- 2Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States
- 3Division of Allergy and Infectious Diseases, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, United States
- 4Department of Global Health, School of Medicine, University of Washington, Seattle, Washington, United States
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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.
Keywords: HIV latency, interferon, Enterocytes, microfold cell (M-cell), Interferon stimulated gene (ISG)
Received: 07 Mar 2025; Accepted: 23 Apr 2025.
Copyright: © 2025 Creighton, Hughes, Hladik and GORNALUSSE. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: German G GORNALUSSE, Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, 98195, Washington, United States
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