Abstract
During antiretroviral therapy (ART) that suppresses HIV replication to below the limit-of-quantification, virions produced during ART can be detected at low frequencies in the plasma, termed residual viremia (RV). We hypothesized that a reservoir of HIV-infected cells actively produce and release virions during ART that are potentially infectious, and that following ART-interruption, these virions can complete full-cycles of replication and contribute to rebound viremia. Therefore, we studied the dynamics of RV sequence variants in 3 participants who initiated ART after ~3 years of infection and were ART-suppressed for >6 years prior to self-initiated ART-interruptions. Longitudinal RV C2V5env sequences were compared to sequences from pre-ART plasma, supernatants of quantitative viral outgrowth assays (QVOA) of cells collected during ART, post-ART-interruption plasma, and ART-re-suppression plasma. Identical, “putatively clonal,” RV sequences comprised 8–84% of sequences from each timepoint. The majority of RV sequences were genetically similar to those from plasma collected just prior to ART-initiation, but as the duration of ART-suppression increased, an increasing proportion of RV variants were similar to sequences from earlier in infection. Identical sequences were detected in RV over a median of 3 years (range: 0.3–8.2) of ART-suppression. RV sequences were identical to pre-ART plasma viruses (5%), infectious viruses induced in QVOA (4%) and rebound viruses (5%) (total n = 21/154 (14%) across the 3 participants). RV sequences identical to ART-interruption “rebound” sequences were detected 0.1–7.4 years prior to ART-interruption. RV variant prevalence and persistence were not associated with detection of the variant among rebound sequences. Shortly after ART-re-suppression, variants that had been replicating during ART-interruptions were detected as RV (n = 5). These studies show a dynamic, virion-producing HIV reservoir that contributes to rekindling infection upon ART-interruption. The persistence of identical RV variants over years suggests that a subpopulation of HIV-infected clones frequently or continuously produce virions that may resist immune clearance; this suggests that cure strategies should target this active as well as latent reservoirs.
Highlights
Antiretroviral therapy (ART) has modified the course of human immunodeficiency virus type-1 (HIV) infection from a largely fatal disease to a chronic, treatable infection with a nearnormal lifespan [1, 2]
HIV-infected individuals receiving effective antiretroviral treatment (ART) produce virions detected in the blood at very low levels, termed residual viremia (RV)
To understand the significance of RV as related to the persistence of HIV infection, we characterized the dynamics of RV sequence variants among plasma viruses over nearly a decade of ART and assessed whether RV contributed to rekindling viremia upon ART-interruption
Summary
Antiretroviral therapy (ART) has modified the course of human immunodeficiency virus type-1 (HIV) infection from a largely fatal disease to a chronic, treatable infection with a nearnormal lifespan [1, 2]. Given that cells capable of producing infectious viruses must be eliminated to cure HIV, many studies have focused on understanding the establishment of this reservoir [5,6,7,8] and the mechanisms that allow it to persist [9,10,11,12]. Studies have revealed essentially stable levels of HIV DNA in the blood [13]; viral variants within the HIV DNA reservoirs appear dynamic [14], and clonally expanded infected cells increase in proportion over time [10, 15]. Our findings suggest that another exception may be clones harboring infectious variants that despite the production of residual viruses, resist immune clearance and contribute to rebound viremia
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