Speaker
Description
Despite effective antiretroviral therapy (ART), HIV-1 persistence remains the principal barrier to a functional cure, driven by long-lived viral reservoirs whose defining features—particularly within tissues—remain poorly understood. Here, we introduce the Virus Microenvironment (VME) as a conceptual framework to explain how HIV-1 establishes, diversifies, and maintains tissue reservoirs that fuel viral rebound.
Using an integrated experimental and computational framework combining viral deep sequencing, immunofluorescence-based viral detection, spatial transcriptomics, cell-type inference, cell–cell interaction analyses, and machine learning, we systematically identified viral, molecular, cellular, and spatial determinants of the VME associated with persistent reservoirs in the SIV/rhesus macaque model.
Following analytical treatment interruption (ATI), viral sequences derived from tissues displayed substantially greater genetic diversity, compartmentalization, lineage turnover, and convergent evolution than matched PBMC-derived sequences. Our analyses demonstrated declining proviral diversity in blood during ART contrasted with preserved and dynamically shifting viral lineages in gut-associated tissues, indicating that non-blood reservoirs maintain complex viral populations under ART and disproportionately seed early viral rebound. Spatially resolved analyses revealed that regions harboring viral foci during early rebound post-ATI were marked by activation of stress-response pathways and translational reprogramming, including disruption of cap-dependent translation, mitochondrial dysfunction, and extracellular matrix remodeling. Spatial cell-type inference linked viral localization to epithelial luminal niches and indicated that persistent reservoirs were uniquely embedded within immune landscapes resembling immunosuppressed germinal center–like structures. By contrast, transient reservoirs were associated with adaptive effector populations consistent with immune-active environments capable of rapid antiviral responses.
Together, these findings support a new tissue reservoir paradigm in which SIV/HIV actively promotes formation of a specialized virus microenvironment that enables local viral replication, diversification, and long-term persistence. The VME represents a physiological sanctuary that sustains rebounding virus while evading immune clearance, highlighting tissue microenvironments as critical targets for curative HIV strategies.
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