Reservoir and Phylogenetic Signatures Identify Distinct Subsets of HIV-1 Nonsuppressible Viremia

In nonsuppressible HIV viremia (NSV), individuals have persistently detectable viral load despite adherence to [&ge;]2 fully active antiretroviral drugs. NSV represents an area of clinical uncertainty and an opportunity to understand the mechanisms of HIV persistence. We performed in-depth virologic characterization to identify distinct NSV phenotypes. We categorized participants into those who had persistent viremia after antiretroviral therapy (ART) initiation (primary NSV) and those who had NSV after a period of virologic suppression (secondary NSV). Despite the prolonged viremia, there was no significant evidence of active viral evolution in either the primary or secondary NSV groups. Primary NSV participants had >10-fold higher levels of intact proviral DNA by the intact proviral DNA assay (P<0.01). While the plasma of secondary NSV participants was dominated by a few large HIV clones, primary NSV participants had far more diverse plasma quasispecies with few clones (P<0.01). Primary NSV participants were also found to harbor distinct deletions within vif-vpr and had T-tropic virus. Transcriptional profiling of intracellular HIV RNA also suggested higher viral transcriptional activity in primary than in secondary NSV. In contrast, profiling of soluble inflammatory markers demonstrated largely comparable systemic inflammatory signatures across NSV subtypes. NSV is comprised of two distinct subsets of individuals, including a novel group with primary NSV characterized by prolonged viremia after ART initiation, an exceptionally large intact reservoir and highly diverse plasma virus populations arising from transcriptionally active proviral reservoirs, without evidence of ongoing evolution. These findings have implications for understanding mechanisms of HIV reservoir persistence on ART. One Sentence SummaryTwo distinct subsets of HIV-1 nonsuppressible viremia, primary and secondary, are identified and characterized by reservoir and phylogenetic characteristics.