Mark D Pankau 1 2, Daniel B Reeves 3, Elias Harkins 4, Keshet Ronen 2, Walter Jaoko 5, Kishor Mandaliya 6, Susan M Graham 2 7 8, R Scott McClelland 2 5 7 8, Frederick A Matsen Iv 4, Joshua T Schiffer 3 7, Julie Overbaugh 1 4, Dara A Lehman 1 2
Affiliations
- 1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
- 2Department of Global Health, University of Washington, Seattle, WA, United States of America.
- 3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
- 4Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
- 5Department of Medical Microbiology, University of Nairobi, Kenyatta National Hospital, Nairobi, Kenya.
- 6Coast Provincial General Hospital, Women’s Health Project, Mombasa, Kenya.
- 7Department of Medicine, University of Washington, Seattle, WA, United States of America.
- 8Department of Epidemiology, University of Washington, Seattle, WA, United States of America.
PMID: 32023326 PMCID: PMC7028291
DOI: 10.1371/journal.ppat.1008286
Abstract
A reservoir of HIV-infected cells that persists despite suppressive antiretroviral therapy (ART) is the source of viral rebound upon ART cessation and the major barrier to a cure. Understanding reservoir seeding dynamics will help identify the best timing for HIV cure strategies. Here we characterize reservoir seeding using longitudinal samples from before and after ART initiation in individuals who sequentially became infected with genetically distinct HIV variants (superinfected). We previously identified cases of superinfection in a cohort of Kenyan women, and the dates of both initial infection and superinfection were determined. Six women, superinfected 0.2-5.2 years after initial infection, were subsequently treated with ART 5.4-18.0 years after initial infection. We performed next-generation sequencing of HIV gag and env RNA from plasma collected during acute infection as well as every ~2 years thereafter until ART initiation, and of HIV DNA from PBMCs collected 0.9-4.8 years after viral suppression on ART. We assessed phylogenetic relationships between HIV DNA reservoir sequences and longitudinal plasma RNA sequences prior to ART, to determine proportions of initial and superinfecting variants in the reservoir. The proportions of initial and superinfection lineage variants present in the HIV DNA reservoir were most similar to the proportions present in HIV RNA immediately prior to ART initiation. Phylogenetic analysis confirmed that the majority of HIV DNA reservoir sequences had the smallest pairwise distance to RNA sequences from timepoints closest to ART initiation. Our data suggest that while reservoir cells are created throughout pre-ART infection, the majority of HIV-infected cells that persist during ART entered the reservoir near the time of ART initiation. We estimate the half-life of pre-ART DNA reservoir sequences to be ~25 months, which is shorter than estimated reservoir decay rates during suppressive ART, implying continual decay and reseeding of the reservoir up to the point of ART initiation.
Conflict of interest statement
The authors have declared that no competing interests exist.
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