bioRxiv2026
HIV reservoirs are heterogeneous across individuals, yet host determinants of this variability remain unclear. Applying multi-omics clustering to 1,230 people with HIV, integrating omics and functional data from circulating immune cells (transcriptomics, DNA methylation, immune phenotyping, ex-vivo cytokine production capacity), plasma proteomics, and CD4+ T-cell reservoir measurements (total and intact HIV-DNA copies), revealed three immunologically distinct endotypes: All Low (low total/low intact reservoir size), All High (high total/high intact reservoir size) and Mixed (high total/low intact reservoir size). Per endotype, distinct immune landscapes were noticed in single-layer analyses as well as differences in clinical signatures. Applying non-linear machine learning across all layers, key predictors not captured by linear single-layer approaches showed IFN-{gamma} production and TCF7/AK5 expression across T-cell and NK-cell populations as well as IL-1{beta}/MCP-1 production after 24h stimulation and MAN1C1/EDAR expression on T-cell populations, linked to intact and total reservoir size, respectively. This host-virus integrative multi-omics framework provides a systems-level resource that may help to personalize reservoir-reducing intervention studies aiming for HIV cure and/or comorbidity reductions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/734029v4_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@16fded7org.highwire.dtl.DTLVardef@18f2e69org.highwire.dtl.DTLVardef@12ffc9borg.highwire.dtl.DTLVardef@17127cc_HPS_FORMAT_FIGEXP M_FIG a) Multi-omics clustering of 1,230 virally suppressed PLHIV identified three immunologically distinct endotypes: All Low (n=428), Mixed (n=483), and All High (n=280), with distinct total and intact HIV reservoir sizes. b) Single-layer analyses reveal characteristic immune landscapes: All Low Th1-skewed, naive T cells (immunophenotyping), high IFN-{gamma} production (7-day), downregulated Type I IFN pathways (bulk transcriptome); Mixed intermediate Th1/Th2, CD8 and CD4 effector memory T cells (immunophenotyping), IL-5 production (7-day), downregulated Type I IFN pathways (bulk transcriptome); All High Th2-skewed, CD4 effector memory T cells (immunophenotyping), high IL-5 production (7-day), upregulated Type I IFN pathways (bulk transcriptome). c) Endotypes carry distinct comorbidity burdens: All Low lower carotid plaque, AIDS-defining malignancies, and residual viremia; Mixed intermediate burden; All High highest carotid plaque, AIDS-defining malignancies, opportunistic infections, and residual viremia. d) Non-linear classification models (XGBoost) prioritize top host predictive markers: IFN-{gamma} response (7-day), TCF7 and AK5 expression in CD4/CD8 T-cells and NK-cells (characterize All Low; IL-1 response (24-hour), MAN1C1 and EDAR in CD4/CD8 T-cells, and MCP1 response (24-hour) characterize All High. Created in BioRender. C_FIG