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

Abstract

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 <1 year for two participants and >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.