Identification of distinct HIV reservoir phenotypes and associated immune landscapes

Virally suppressed people with HIV (PWH) remain at risk for developing comorbidities due to chronic inflammation with one potential contributor being the HIV reservoirAssociations between the CD4 reservoir and inflammation have been extensively characterized, while the role the monocyte reservoir is poorly understood despite evidence that inflammatory monocytes play a role in HIV-associated comorbidities. Additionally, most studies focus on a single cellular reservoir, while it is highly likely that these reservoirs are interdependent. In a cohort of 164 PWH, we used the intact proviral DNA assay to quantify cell-specific reservoirs, applied unsupervised clustering to identify reservoir phenotypes, and then determined if reservoir phenotypes were associated with distinct immune signatures compared with people without HIV. Five unique reservoir clusters emerged, driven primarily by variability in the monocyte reservoir, and each associated with a distinct immune landscape. These included profiles characterized by systemic inflammation, leukocyte-vascular activation, T cell activation with vascular and neuronal injury, enhanced CD8 activation and NK cell recovery, and altered monocyte survival, activation, and migration. This multidimensional approach provides a framework to identify reservoir-immune profiles that may explain heterogeneity in inflammation, despite viral suppression and may inform strategies to mitigate HIV-associated comorbidities.