HIV-1 subtype A1, D, and recombinant proviral genome landscapes during long-term suppressive therapy.
Guinevere Q LeePragya KhadkaSarah N GowanlockDennis C CopertinoMaggie C DuncanF Harrison OmondiNatalie N KinlochJingo KasuleTaddeo KityamuweesiPaul BuuleSamiri JamiruStephen TomusangeAggrey AnokZhengming ChenR Brad JonesRonald M GaliwangoSteven J ReynoldsThomas C QuinnZabrina L BrummeAndrew D ReddJessica L ProdgerPublished in: Nature communications (2024)
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.
Keyphrases
- antiretroviral therapy
- hiv infected
- hiv positive
- human immunodeficiency virus
- hiv aids
- hiv infected patients
- hiv testing
- hepatitis c virus
- men who have sex with men
- south africa
- cell free
- single molecule
- magnetic resonance
- copy number
- gene expression
- high throughput
- genome wide
- small molecule
- heart rate
- dna methylation
- bone marrow
- mouse model
- fluorescence imaging
- induced apoptosis
- loop mediated isothermal amplification
- fluorescent probe
- heart rate variability
- quantum dots
- liquid chromatography
- ms ms