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Dynamics of HIV DNA reservoir seeding in a cohort of superinfected Kenyan women.

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.

SUBMITTER: Pankau MD

PROVIDER: S-EPMC7028291 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Dynamics of HIV DNA reservoir seeding in a cohort of superinfected Kenyan women.

Pankau Mark D MD Reeves Daniel B DB Harkins Elias E Ronen Keshet K Jaoko Walter W Mandaliya Kishor K Graham Susan M SM McClelland R Scott RS Matsen Iv Frederick A FA Schiffer Joshua T JT Overbaugh Julie J Lehman Dara A DA

PLoS pathogens 20200205 2

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 previousl ...[more]

PMID: 32023326

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Project description:HIV superinfection (reinfection) has been reported in several settings, but no study has been designed and powered to rigorously compare its incidence to that of initial infection. Determining whether HIV infection reduces the risk of superinfection is critical to understanding whether an immune response to natural HIV infection is protective. This study compares the incidence of initial infection and superinfection in a prospective seroincident cohort of high-risk women in Mombasa, Kenya. A next-generation sequencing-based pipeline was developed to screen 129 women for superinfection. Longitudinal plasma samples at <6 months, >2 years and one intervening time after initial HIV infection were analyzed. Amplicons in three genome regions were sequenced and a median of 901 sequences obtained per gene per timepoint. Phylogenetic evidence of polyphyly, confirmed by pairwise distance analysis, defined superinfection. Superinfection timing was determined by sequencing virus from intervening timepoints. These data were combined with published data from 17 additional women in the same cohort, totaling 146 women screened. Twenty-one cases of superinfection were identified for an estimated incidence rate of 2.61 per 100 person-years (pys). The incidence rate of initial infection among 1910 women in the same cohort was 5.75 per 100 pys. Andersen-Gill proportional hazards models were used to compare incidences, adjusting for covariates known to influence HIV susceptibility in this cohort. Superinfection incidence was significantly lower than initial infection incidence, with a hazard ratio of 0.47 (CI 0.29-0.75, p?=?0.0019). This lower incidence of superinfection was only observed >6 months after initial infection. This is the first adequately powered study to report that HIV infection reduces the risk of reinfection, raising the possibility that immune responses to natural infection are partially protective. The observation that superinfection risk changes with time implies a window of protection that coincides with the maturation of HIV-specific immunity.

Project description:IntroductionThe postpartum period can be challenging for women living with HIV. Understanding how the postpartum period impacts ART adherence and condomless sex could inform the development of comprehensive sexual and reproductive health and HIV services tailored to the needs of women living with HIV during this critical interval.MethodsIn a longitudinal cohort study of HIV-seropositive Kenyan women, late ART refills and self-reported condomless sex were compared between the woman's pregnancy and the postpartum period. Analyses were conducted using generalized estimating equations and adjusted for alcohol use, depressive symptoms, intimate partner violence (IPV), and having a recent regular partner. Effect modification was explored for selected variables.Results and discussion151 women contributed visits. Late ART refills occurred at 7% (32/439) of pregnancy visits compared to 18% (178/1016) during the postpartum period (adjusted relative risk [aRR] 2.44, 95% confidence interval [CI] 1.62-3.67). This association differed by women's education level. Women with ≥8 years of education had late ART refills more during the postpartum period than pregnancy (aRR 3.00, 95%CI 1.95-4.62). In contrast, in women with <8 years of education, late ART refills occurred similarly during pregnancy and the postpartum period (aRR 0.88, 95%CI 0.18-4.35). Women reported condomless sex at 10% (60/600) of pregnancy visits compared to 7% (72/1081) of postpartum visits (aRR 0.76, 95%CI 0.45-1.27). This association differed by whether women had experienced recent IPV. Women without recent IPV had a significant decline in condomless sex from pregnancy to postpartum (aRR 0.53, 95%CI 0.30-0.95) while women with recent IPV had no significant change in condomless sex from pregnancy to postpartum (aRR 1.76, 95%CI 0.87-3.55).ConclusionImproved support for ART adherence during the postpartum period and addressing IPV to limit condomless sex could improve HIV treatment and prevention outcomes for HIV-seropositive women as well as their infants and sexual partners.

Project description:BACKGROUND:Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-?, IFN-?/?, and other pro-inflammatory cytokines. METHODS:Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (M?) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. RESULTS:In vivo, both doses of 10 and 50?mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII+/CD45+) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p?<?0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in M?. CONCLUSION:These results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.

Dataset Information

Dynamics of HIV DNA reservoir seeding in a cohort of superinfected Kenyan women.

Publications

Dynamics of HIV DNA reservoir seeding in a cohort of superinfected Kenyan women.

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