Genomic landscape of HIV-1 proviruses in ART-treated immunological non-responders

Immunological non-responders (INRs) and immunological responders (IRs) exhibit distinct patterns of immune reconstitution despite suppressive antiretroviral therapy (ART); however, the genetic characteristics of the HIV-1 reservoir in these groups remain poorly understood. This study investigates the landscape of HIV-1 proviruses in INRs and IRs, and its potential association with immune reconstitution.

Peripheral blood mononuclear cells (PBMCs) from 10 ART-treated INRs and 10 IRs were analyzed using near-full-length HIV-1 DNA amplification and PacBio third-generation sequencing to characterize genetically intact and defective proviral genomes. Intact open reading frames (ORFs) were further inferred using the CFEIntact tool.

Compared with IRs, INRs had a higher total proviral genome per 10⁶ PBMCs, although the difference did not reach statistically significance. INRs also displayed a significantly higher level of intact proviral genomes per 10⁶ PBMCs and a trend toward a higher proportion of intact sequences. Defective proviruses remained the predominant component of the reservoir in both groups and were broadly comparable in number and composition. In both cohorts, proviral defects were more frequently observed in the 3' half of the genome.

Our study reveals a distinct proviral landscape in ART-treated INRs, characterized by elevated levels of intact proviral genomes. These observations suggest that the intact component of the reservoir may represent a clinically relevant feature of incomplete immune reconstitution, and provide a rationale for further studies of reservoir-directed interventions in this population.