HIV-1 subtype A1, D, and recombinant proviral genome landscapes during long- term suppressive therapy

July 2, 2024 by
HIV-1 subtype A1, D, and recombinant proviral genome landscapes during long- term suppressive therapy
Aber Maurine
Guinevere Q. Lee1; Pragya Khadka1; Sarah N. Gowanlock2; Dennis C. Copertino Jr1; Maggie C. Duncan3,4; F. Harrison Omondi3,4; Natalie N. Kinloch3,4; Jingo Kasule5; Taddeo Kityamuweesi5; Paul Buule5; Samiri Jamiru5; Stephen Tomusange5; Aggrey Anok5; Zhengming Chen6; R. Brad Jones1; Ronald M. Galiwango5; Steven J. Reynolds5,7,8; Thomas C. Quinn7,8; Zabrina L. Brumme3,4; Andrew D. Redd7,8,9,11 & Jessica L. Prodger2,10,11

Affiliations:

1Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA
2Department of Microbiology and Immunology, Western University, London, ON, Canada
3Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada
4British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada
5Rakai Health Sciences Program, Kalisizo, Uganda
6Department of Population Health Sciences, Division of Biostatistics, Weill Cornell Medicine, New York, NY, USA
7Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
8Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
9Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
10Department of Epidemiology and Biostatistics, Western University, London, ON, Canada
11These authors contributed equally: Andrew D. Redd, Jessica L. Prodger

Corresponding author: gul4001@med.cornell.edu


The primary obstacle to curing HIV-1 is a reservoir of CD4+ cells that contain stably integrated provirus. Previous studies characterizing the proviral landscape, which have been predominantly conducted in males in the United States and Europe living with HIV-1 subtype B, have revealed that most proviruses that persist during antiretroviral therapy (ART) are defective. In contrast, less is known about proviral landscapes in females with non-B subtypes, which represents the largest group of individuals living with HIV-1. 


Here, we analyze genomic DNA from resting CD4+ T-cells from 16 female and seven male Ugandans with HIV-1 receiving suppressive ART (n = 23). We perform near-full-length proviral sequencing at limiting dilution to examine the proviral genetic landscape, yielding 607 HIV-1 subtype A1, D, and recombinant proviral sequences (mean 26/person). We observe that intact genomes are relatively rare and clonal expansion occurs in both intact and defective genomes. Our modification of the primers and probes of the Intact Proviral DNA Assay (IPDA), developed for subtype B, rescues intact provirus detection in Ugandan samples for which the original IPDA fails. 


This work will facilitate research on HIV-1 persistence and cure strategies in Africa, where the burden of HIV-1 is heaviest.


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