HIV DNA and transcription before and after ART in natural controllers compared to noncontrollers

HIV-1 natural controllers can limit plasma HIV RNA levels in the absence of antiretroviral therapy (ART). Although controllers have less HIV DNA, it remains unclear how HIV transcription differs from noncontrollers, and whether ART further reduces HIV DNA or RNA in controllers. To address these questions, we quantified different HIV transcripts and HIV DNA regions/proviruses in longitudinal blood samples collected before ART and up to 3-5 years on suppressive ART from 10 controllers (5 "elite" and 5 viremic) and compared them to ART-suppressed noncontrollers. Compared to noncontrollers, controllers exhibited lower levels of most HIV DNA regions (but not intact proviruses) and lower total levels of initiated and completed HIV RNA, but paradoxically higher levels per provirus of initiated and 5' elongated HIV transcripts. Controllers also showed a lower ratio of completed/elongated HIV RNA. After ART, controllers showed lower levels of multiply spliced HIV RNA and a lower ratio of multiply spliced/completed HIV RNA. These results suggest that natural controllers limit HIV infection frequency and selectively restrict HIV transcript completion and splicing. ART treatment of controllers led to further increases in CD4 counts and decreases in HIV DNA and some HIV transcripts, supporting the potential for clinical benefits in this population.IMPORTANCENatural HIV controllers can suppress HIV-1 replication without antiretroviral therapy (ART) and serve as a model for an HIV functional cure, but the mechanisms are unclear. We found that natural control was associated with mechanisms that reduce levels of total HIV DNA and the HIV promoter regions to below the levels seen in ART-treated noncontrollers (NC), resulting in lower total levels of most HIV transcripts. When corrected for HIV DNA levels, natural controllers exhibited higher levels per provirus of short, prematurely terminated HIV transcripts but lower proportions of completed and spliced HIV transcripts. These findings suggest that the mechanisms of natural control do not only limit HIV infection frequency, but specifically limit production or increase clearance of infected cells making completed and spliced HIV transcripts. ART treatment of controllers led to further increases in CD4⁺ T-cell counts and decreases in HIV DNA and RNA, suggesting that ART should be offered to controllers.