The liver as an immune organ in HIV infection: pathogenesis and clinical implications

Background The liver’s role in human immunodeficiency virus (HIV) infection has been historically undervalued, often viewed through the lens of co-infections or drug toxicity. Emerging evidence now positions the liver as a critical immune organ, actively shaping HIV pathogenesis through its unique cellular composition and immunological functions. Objective This review synthesizes current knowledge to argue that the liver is a central site of HIV persistence and chronic inflammation. It aims to detail the mechanisms of hepatic immune subversion and their direct clinical consequences in the antiretroviral therapy (ART) era. Methods We conducted a systematic analysis of contemporary literature, focusing on studies investigating hepatic reservoirs, immune cell dysfunction, microbial translocation, and the resulting inflammatory and fibrotic pathways in both HIV-mono-infected and co-infected individuals. Results The liver constitutes a significant sanctuary for HIV, harboring latently infected Kupffer cells and T-cells. HIV subverts the liver’s tolerogenic state, driving chronic inflammation through mechanisms including persistent microbial translocation and direct activation of hepatic stellate cells. This pathological remodeling accelerates liver fibrosis in mono-infected individuals and contributes to systemic non-AIDS comorbidities, including cardiovascular and metabolic disease. The efficacy of cure strategies and drug metabolism are further complicated by this altered hepatic immune environment. Conclusion The liver is a significant actor in HIV immunopathogenesis, not a passive bystander. Its dysfunction underpins key clinical challenges in managing people living with HIV. Future research must prioritize liver-targeted therapeutic interventions and the development of non-invasive biomarkers to improve long-term patient outcomes.