Editorial: HIV and the gut: novel insights into HIV pathogenesis, clinical implications and therapeutic approaches

The gastrointestinal tract is increasingly recognized as a central player in HIV pathogenesis. From the earliest stages of infection, HIV profoundly disrupts the intestinal epithelial barrier and gut-associated lymphoid tissue (GALT), leading to microbial dysbiosis and translocation, and persistent immune activation, despite effective antiretroviral therapy (ART) (1,2). Severe depletion of CD4+ T cells, particularly Th17 cells, together with an altered Treg/Th17 balance, compromises mucosal integrity and sustains chronic inflammation, while the gut remains a major reservoir for HIV (3, 4). Collectively, these alterations contribute not only to viral persistence but also to the development of multiple HIVassociated comorbidities.The original research articles and reviews, collected in this Research Topic, provide new insights into the immunological, metabolic-and microbiota-driven mechanisms linking HIV infection to gut dysfunction.A major barrier to HIV cure is the persistence of long-lived latent reservoirs that evade immune clearance and ART. Among all tissues, the gastrointestinal tract, particularly GALT, harbors the majority of infected cells even under suppressive ART. Lau et al. present the gut not as a passive reservoir but as an active driver of HIV latency, immune activation, and reservoir maintenance during long-term ART. Early in infection, HIV induces rapid and profound depletion of CCR5⁺ memory CD4⁺ T cells, including Th17 and Th22 subsets that are critical for maintaining epithelial integrity. This damage initiates a cycle of barrier dysfunction, microbial translocation, and inflammation that persists despite ART. Rather than resolving, persistent immune activation sustains viral reservoirs and continuously generates new HIV-susceptible target cells. The authors highlight gut-enriched cellular reservoirs, including CCR6⁺ CD4⁺ T cells and tissue-resident memory T cells, which exhibit deep latency, long lifespan, and limited accessibility to immune-mediated clearance. Although multiple strategies have been explored, ranging from latency-reversing agents and immune-based therapies to microbiome modulation and trafficking inhibitors, none have achieved so far durable reduction of gut reservoirs.Expanding on the role of the epithelial compartment,