HIV proviral burden, genetic diversity and dynamics in viremic controllers who subsequently initiated suppressive antiretroviral therapy

Curing HIV will require eliminating the reservoir of integrated, replication-competent proviruses that persist despite antiretroviral therapy. Understanding the burden, genetic diversity and longevity of persisting proviruses in diverse individuals with HIV is critical to this goal, but these characteristics remain understudied in some groups. Viremic controllers, individuals who naturally suppress HIV to low levels but for whom therapy is nevertheless recommended, represent one such group who could yield insights into proviral seeding and turnover in the setting of natural yet incomplete HIV control. We reconstructed within-host HIV evolutionary histories from single-genome amplified viral sequences in four viremic controllers who eventually initiated therapy, and leveraged this information to characterize the diversity and longevity of proviruses persisting on therapy. Despite natural viremic control, all participants displayed significant within-host HIV evolution pre-therapy, where the overall burden and diversity of proviruses persisting on therapy reflected the extent of viral replication, and plasma viral diversity generated, during untreated infection. While the proviral pools of two participants were skewed towards sequences that integrated near ART initiation, proviruses in the other two participants dated to various time-points that were more evenly spread throughout infection and included sequences that integrated close to transmission. Estimated in vivo proviral half-lives were 2 years for a third, consistent with dynamic proviral turnover during untreated infection; the fourth was consistent with negligible proviral decay following deposition. HIV cure strategies will need to overcome within-host proviral diversity, even in individuals who naturally controlled HIV replication before therapy. ImportanceHIV therapy is life-long because integrated, replication-competent viral copies persist within long-lived cells. To cure HIV, we need to understand when these viral reservoirs form, how large and genetically diverse they are, and how long they endure in vivo. Elite controllers, individuals who naturally suppress HIV to undetectable levels, have been intensely studied, in part because their small reservoirs may make HIV eradication more achievable. Viremic controllers, individuals who naturally suppress HIV to low levels, may also hold insights but remain understudied. We used a phylogenetic approach to reconstruct reservoir seeding and decay in four viremic controllers from infection to HIV suppression on therapy. In all participants, we recovered diverse HIV sequences persisting during therapy that broadly reflected HIVs evolutionary history during untreated infection. Even in individuals who naturally controlled HIV replication prior to therapy, HIV cure strategies will need to contend with diverse proviral variants archived throughout infection.