HIV Proviral Burden, Genetic Diversity, and Dynamics in Viremic Controllers Who Subsequently Initiated Suppressive Antiretroviral Therapy
F. Harrison Omondi, Hanwei Sudderuddin, Aniqa Shahid, Natalie N. Kinloch, Bradley R. Jones, Rachel L. Miller, Olivia Tsai, Daniel MacMillan, Alicja Trocha, Mark A. Brockman, Chanson J. Brumme, Jeffrey B. Joy, Richard Liang, Bruce D. Walker, Zabrina L. Brumme
Abstract
HIV therapy is lifelong 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. Elite controllers-individuals who naturally suppress HIV to undetectable levels-are being intensely studied as models of HIV remission, but viremic controllers, individuals who naturally suppress HIV to low levels, remain understudied even though they too may hold valuable insights. We combined phylogenetics and mathematical modeling to reconstruct proviral seeding and decay from infection to therapy-mediated suppression in four viremic controllers. We recovered diverse proviruses persisting during therapy that broadly reflected HIV's within-host evolutionary history, where the estimated half-lives of the persistent proviral pool during untreated infection ranged from <1 year to negligible. Cure strategies will need to contend with proviral diversity and between-host heterogeneity, even in individuals who naturally control HIV.