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

• Published in: Nature communications Vol. 15; no. 1; pp. 5480 - 10
• Main Authors: Lee, Guinevere Q., Khadka, Pragya, Gowanlock, Sarah N., Copertino, Dennis C., Duncan, Maggie C., Omondi, F. Harrison, Kinloch, Natalie N., Kasule, Jingo, Kityamuweesi, Taddeo, Buule, Paul, Jamiru, Samiri, Tomusange, Stephen, Anok, Aggrey, Chen, Zhengming, Jones, R. Brad, Galiwango, Ronald M., Reynolds, Steven J., Quinn, Thomas C., Brumme, Zabrina L., Redd, Andrew D., Prodger, Jessica L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 45; 45/23; 45/77; 631/326/596/2564; 692/699/255/2514; Adult; Anti-HIV Agents - therapeutic use; Antiretroviral agents; Antiretroviral therapy; CD4 antigen; CD4-Positive T-Lymphocytes - virology; Deoxyribonucleic acid; Dilution; DNA; DNA probes; DNA, Viral - genetics; Drug therapy; Female; Females; Genome, Viral - genetics; Genomes; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - classification; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Lymphocytes T; Male; Males; multidisciplinary; Nucleotide sequence; Proviruses; Proviruses - genetics; Science; Science (multidisciplinary); Therapy; Uganda; Viral Load; Uganda
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48985-9

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. Most studies on HIV-1 proviruses that persist during antiretroviral therapy have focused on males with HIV-1 subtype B, even though the majority of people living with HIV globally have non-B subtypes. Here, the authors describe the proviral genetic landscape of HIV-1 subtypes A1 and D in Ugandan females and males using near-full-length proviral sequencing. The authors also describe a molecular assay for intact proviral quantification of these HIV-1 subtypes.