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The principal barrier to an HIV cure is the presence of a latent viral reservoir (LVR) made up primarily of latently infected resting CD4+ (rCD4) T-cells. Studies in the United States have shown that the LVR decays slowly (half-life=3.8 years), but this rate in African populations has been understudied. This study examined longitudinal changes in the inducible replication competent LVR (RC-LVR) of ART-suppressed Ugandans living with HIV (n=88) from 2015-2020 using the quantitative viral outgrowth assay, which measures infectious units per million (IUPM) rCD4 T-cells. In addition, outgrowth viruses were examined with site-directed next-generation sequencing to assess for possible ongoing viral evolution. During the study period (2018-19), Uganda instituted a nationwide rollout of first-line ART consisting of Dolutegravir (DTG) with two NRTI, which replaced the previous regimen that consisted of one NNRTI and the same two NRTI. Changes in the RC-LVR were analyzed using two versions of a novel Bayesian model that estimated the decay rate over time on ART as a single, linear rate (model A) or allowing for an inflection at time of DTG initiation (model B). Model A estimated the population-level slope of RC-LVR change as a non-significant positive increase. This positive slope was due to a temporary increase in the RC-LVR that occurred 0-12 months post-DTG initiation (pAuthor SummaryHIV is a largely incurable infection despite the use of highly successful antiretroviral drugs (ARV) due to the presence of a population of long-living resting CD4+ T cells, which can harbor a complete copy of the virus integrated into the host cell’s DNA. We examined changes in the levels of these cells, referred to as the latent viral reservoir, in a group of ARV-treated Ugandans living with HIV. During this examination, Uganda authorities switched the backbone drug used in ARV regimens to a different class of drug that blocks the ability of the virus to integrate into the cell’s DNA. We found that for approximately a year after this switch to the new drug, there was a temporary spike in the size of the latent viral reservoir despite the new drug continuing to completely suppress viral replication with no apparent adverse clinical effects.

HIV-1 infection remains incurable owing to the persistence of a viral reservoir that harbors integrated provirus within host cellular DNA. Increasing evidence links sex-based differences in HIV-1 immune responses and pathogenesis; however, little is known about differences in HIV-1 infection persistence. Here, we quantified persistent HIV-1 infection in 90 adults on suppressive antiretroviral therapy in Rakai, Uganda (57 female patients). Total HIV-1 DNA was quantified by PCR, and replication-competent provirus by quantitative viral outgrowth assay (QVOA). Immune phenotyping of T cell subsets and plasma biomarkers was also performed. We found that whereas both sexes had similar total HIV DNA levels, female patients had significantly fewer resting CD4(+) T cells harboring replication-competent virus, as measured by viral outgrowth in the QVOA. Factors associated with viral outgrowth differed by sex; notably, frequency of programmed cell death 1 (PD1(+)) CD4(+) T cells correlated with reservoir size in male but not female patients. The sex-based differences in HIV-1 persistence observed in this cohort warrant additional research, especially given the widespread use of the QVOA to assess reservoir size and current explorations of PD1 agonists in cure protocols. Efforts should be made to power future cure studies to assess outcomes in both male and female patients.

Background Human immunodeficiency virus type 1 (HIV-1) persists in latently infected resting CD4+ T cells (rCD4 cells), posing a major barrier to curing HIV-1 infection. Previous studies have quantified this pool of latently infected cells in Americans; however, no study has quantified this reservoir in sub-Saharan Africans, who make up the largest population of HIV-1-infected individuals globally. Methods Peripheral blood was collected from 70 virally suppressed HIV-1-infected individuals from Rakai District, Uganda, who had initiated antiretroviral therapy (ART) during chronic infection. The quantitative viral outgrowth assay was used to determine frequency of latently infected rCD4 cells containing replication-competent virus. Multivariate regression was used to identify correlates of reservoir size and to compare reservoir size between this Ugandan cohort and a previously studied cohort of individuals from Baltimore, Maryland. Results The median frequency of latently infected rCD4 cells in this Ugandan cohort was 0.36 infectious units per million cells (IUPM; 95% confidence interval, 0.26-0.55 IUPM), 3-fold lower than the frequency observed in the Baltimore cohort (1.08 IUPM; .72-1.49 IUPM; P < .001). Reservoir size in Ugandans was correlated positively with set-point viral load and negatively with duration of viral suppression. Conclusions Virally suppressed Ugandans had a 3-fold lower frequency of rCD4 cells latently infected with replication-competent HIV-1, compared with previous observations in a cohort of American patients, also treated with ART during chronic infection. The biological mechanism driving the observed smaller reservoir in Ugandans is of interest and may be of significance to HIV-1 eradication efforts.