The Gut–Immune Axis in Treated HIV Infection: From Mucosal Damage to Chronic Inflammation and Therapeutic Opportunities—A Clinician-Oriented Narrative Review

Combined antiretroviral therapy (cART) has transformed HIV into a manageable chronic disease. However, people living with HIV (PLWH) experience a 16-year reduction in comorbidity-free life expectancy compared to HIV-negative individuals, driven by persistent chronic immune activation despite virological suppression. Serious non-AIDS events (SNAEs)—including cardiovascular disease, metabolic disorders, and malignancies—now represent the predominant cause of morbidity. This narrative review provides a clinician-oriented synthesis of immunopathophysiological mechanisms driving chronic inflammation in treated HIV infection, focusing on the gut–immune axis, restriction factors, trained immunity, biomarker-guided risk stratification, and therapeutic strategies. We searched PubMed/MEDLINE, Embase, and Web of Science through April 2026 using terms related to HIV chronic immune activation, gut-associated lymphoid tissue, microbial translocation, inflammaging, restriction factors, trained immunity, and biomarkers. This review followed the SANRA checklist. Irreversible destruction of gut-associated lymphoid tissue (GALT), intestinal barrier dysfunction, microbial translocation, maladaptive trained immunity, persistent myeloid activation with NLRP3 inflammasome signaling and cellular senescence, and viral reservoir persistence collectively perpetuate systemic inflammation. Biomarkers, including sCD14, IL-6, and suPAR, independently predict mortality but are not pathogen-specific. The REPRIEVE trial demonstrated a 36% reduction in cardiovascular risk with pitavastatin (HR 0.64, 95% CI 0.48–0.84), validating inflammation as a therapeutic target. Integration of early cART, statin therapy, optimal antiretroviral selection, and emerging strategies—including GLP-1 receptor agonists and gut-directed therapies—offers a practical framework for reducing inflammation-associated comorbidities in virologically suppressed PLWH.