The Human Virome in Health and Its Remodeling During HIV Infection and Antiretroviral Therapy: A Narrative Review

The human virome represents a fundamental yet understudied component of the microbiome, influencing immune regulation and disease. Given the profound immune dysregulation and microbial imbalance associated with HIV infection, understanding virome alterations during HIV and antiretroviral therapy is essential. This narrative review seeks to integrate and discuss the latest evidence regarding the structure and behavior of the human virome in healthy individuals, in the context of HIV infection, and under antiretroviral therapy. A comprehensive literature search was performed in MEDLINE and Google Scholar for peer-reviewed English-language articles published up to November 2025. Studies describing virome composition, diversity, and interactions in people living with HIV, as well as antiretroviral-induced changes, were included. Reference lists of relevant papers were screened to identify additional sources. Data were extracted and synthesized narratively, emphasizing human studies and supported by evidence from primate models where applicable. HIV infection induces profound alterations in the human virome, notably an expansion of eukaryotic viruses such as <i>Anelloviridae</i>, <i>Adenoviridae</i>, and <i>Parvoviridae</i>, accompanied by reduced bacteriophage diversity. Antiretroviral therapy partially restores virome balance but fails to fully re-establish pre-infection diversity, with persistent enrichment of <i>Anelloviridae</i> reflecting incomplete immune reconstitution. Virome perturbations correlate with immune activation, microbial translocation, and inflammation, contributing to comorbidities despite virological suppression. Emerging evidence suggests regimen-specific effects, with integrase inhibitor-based therapies showing more favorable viromic recovery. HIV and antiretroviral therapy profoundly remodel the human virome, with lasting implications for immune homeostasis and chronic inflammation. The ongoing disruption of the virome highlights its promise as both a biomarker and a potential therapeutic target in the management of HIV. Longitudinal, multi-omic studies are needed to clarify the causal role of virome alterations and guide future interventions.