Dynamics of HIV DNA reservoir seeding in a cohort of superinfected Kenyan women.
PLoS Pathog
; 16(2): e1008286, 2020 02.
Article
in En
| MEDLINE
| ID: mdl-32023326
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phylogeny
/
DNA, Viral
/
HIV Infections
/
HIV-1
/
Gag Gene Products, Human Immunodeficiency Virus
/
Env Gene Products, Human Immunodeficiency Virus
Type of study:
Clinical_trials
/
Observational_studies
/
Prognostic_studies
Limits:
Adult
/
Female
/
Humans
Country/Region as subject:
Africa
Language:
En
Journal:
PLoS Pathog
Year:
2020
Document type:
Article
Affiliation country:
United States