Fredrick Harrison Omondi, Simon Fraser University

F. Harrison Omondia,b, Aniqa Shahida,b, Natalie N. Kinlocha,b, Winnie Dongb, Maggie C. Duncana,b, Fatima Yaseenb, Evan Barada,b, Nadia Moranb, Amanda Cabral da Silvaa,b, Vitaliy Mysakb, Don Kirkbyb, Mario Ostrowskie, Rebecca M. Lynchd, Chanson J. Brummeb,g, Colin Kovacsg, R. Brad Jonesc, Guinevere Q. Leec, Zabrina L. Brummea,b# a Faculty of Health Sciences, Simon Fraser University, Burnaby, BC b British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC c Infectious Disease Division, Department of Medicine, Weill Cornell Medical College, New York, NY d Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, D.C. e Department of Immunology, University of Toronto, Toronto, ON f Department of Medicine, University of British Columbia, Vancouver, Canada g Maple Leaf Clinic, Toronto, ON

Expressing & Multiplying

HIV superinfection, where an individual living with HIV acquires a second phylogenetically distinct strain, provides a unique opportunity to study reservoir establishment and rebound dynamics because the two strains can be tracked over time. We characterized a case of HIV superinfection discovered retrospectively after enrolment in a research study. The participant, who expressed the protective HLA-B*57:03 allele, initially controlled his subtype B infection. But, viremic control was lost after superinfection with a unique recombinant form (URF) featuring a subtype G/CRF02_AG mosaic genome, which came to dominate in plasma without displacing the original B strain. After five years of suppressive therapy, URF proviruses dominated in blood CD4 T-cells (80%), though replication-competent sequences from both B and URF strains were recovered. Despite their unequal representation in the reservoir, both strains appeared in plasma within 11 days after treatment interruption, though a subclade of URF sequences that predated ART initiation dominated the rebound. Consistent with "waves" of reactivation of distinct reservoir cells (or cell clones), genetically distinct viral lineages continued to appear during the treatment interruption. Analysis of HLA-B*57:03-restricted epitopes suggested the URF transmitted/founder virus already harbored key escape mutations, likely explaining the loss of initial viral control and subsequent URF dominance. We also observed evidence of de novo escape during the rebound. Overall, this case demonstrates that HIV superinfection can remain undetected by routine clinical monitoring and highlights that initial rebound sequences do not necessarily reflect blood proviral abundance during long-term HIV therapy, nor plasma diversity immediately prior to ART.