HIV-driven virome dysbiosis unveils distinct virome features and inter-viral correlations in blood and respiratory niches.

While systemic immune dysregulation is well-documented in HIV infection, its impact on blood and respiratory tract viromes remains poorly understood. This study characterizes HIV-associated alterations in viral communities and examines their clinical relevance. Using viral metagenomics, we compare 203 ART-treated HIV-positive individuals and 120 healthy controls. HIV infection significantly restructures the blood virome, shifting from bacteriophage dominance (96.2% in controls) to eukaryotic virus predominance (69.1%). Increased alpha diversity, significant β-diversity divergence, and heightened dispersion heterogeneity are observed in HIV cases. Consistent enrichment of Flaviviridae, Parvoviridae, and Anelloviridae is detected. Throat viromes maintain phage dominance (>90%) but exhibit strain-level diversification, including Microviridae proliferation. Network analysis reveals Retroviridae-Anelloviridae co-dynamics (r = +0.562) and identifies Picobirnaviridae as a key interactor. Functional analysis shows enriched viral replication and host modulation genes. Compartment-specific disruption patterns nominate Pegivirus C, parvovirus B19, and Anelloviruses as potential biomarkers. Cross-kingdom viral interactions suggest novel mechanisms influencing disease progression and support future virome-targeting adjunct therapies.