Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen
Authors: Ferreira Roux-Cil , Reynolds Steven J. , Capoferri Adam A. , Baker Owen , Brown Erin E. , Klock Ethan , Miller Jernelle , Lai Jun , Saraf Sharada , Kirby Charles , Lynch Briana , Hackman Jada , Gowanlock Sarah N. , Tomusange Stephen , Jamiru Samiri , Anok Aggrey , Kityamuweesi Taddeo , Buule Paul , Bruno Daniel , Martens Craig , Rose Rebecca , Lamers Susanna L. , Galiwango Ronald M. , Poon Art F. Y. , Quinn Thomas C. , Prodger Jessica L. , Redd Andrew D. 
Published: May 2023

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 (p<0.0001). This was confirmed with model B, which estimated a significant decay pre-DTG initiation with a half-life of 7.7 years, but a significant positive slope post-DTG initiation leading to a transient estimated doubling-time of 8.1 years. There was no evidence of viral failure in the cohort, or consistent evolution in the outgrowth sequences associated with DTG initiation. These data suggest that either the initiation of DTG, or cessation of NNRTI use, is associated with a significant temporary increase in the circulating RC-LVR.

Author Summary

HIV 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.