Fredrick Harrison Omondi, Simon Fraser University

F. Harrison Omondi a,b, Yurou Sang a, Winnie Dong b, Francis Mwimanzi a, Peter K. Cheung a,b, Evan Barad a,b, Zerufael Derza a, Kieran Anderson e, Aniqa Shahid a,b, Vitaliy Mysak b, Viviane D. Lima b,c, Mark Hull c,f, Chanson J. Brumme b,c, Marianne Harris b,d, Julio S.G. Montaner b,c, Silvia Guillemi b,d, Mark A. Brockman a,b,e, Zabrina L. Brumme a,b# a Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada b British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada c Department of Medicine, University of British Columbia, Vancouver, Canada d Department of Family Practice, Faculty of Medicine, University of British Columbia, Vancouver, Canada e Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada f Division of Infectious Diseases, Providence Health Care, Vancouver, Canada

Expressing & Multiplying

Antiretroviral therapy (ART) potently inhibits HIV replication but does not eliminate HIV proviruses integrated within the genomes of infected cells. Though ART normally suppresses HIV to clinically undetectable levels in blood, some individuals experience non-suppressible viremia (NSV) that is not attributable to suboptimal drug exposure (e.g. incomplete medication adherence or pharmacological issues) nor emerging HIV drug resistance, and that does not resolve following ART regimen modification. We now understand that NSV can originate from expanded cell clones harboring genetically identical proviruses that reactivate to produce clinically detectable viremia. NSV can even originate from proviruses with genomic defects, particularly within HIV's major splice donor (MSD) site, which render the viremia non-infectious. But, because only a limited number of such cases have been described, all in HIV subtype B, the mechanisms that allow cells harboring such proviruses to produce prolonged viremia without being eliminated remain incompletely understood. We characterized a case of MSD-defective, replication-impaired NSV that lasted >4 years in an individual with non-B HIV. Our results reveal that proviruses with MSD deletions can persist by integrating into minimally differentiated CD4 T-cell subsets that then give rise to the full spectrum of memory and effector subpopulations, and by exhibiting an HIV protein expression profile that would allow these cells to evade both cellular and humoral immunity. Our results highlight the need to better understand the biological implications of persistent HIV protein and virion production by clonally expanded cells harboring genomically defective proviruses, and for clinical guidelines to acknowledge this type of viremia.