Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen
Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen
Abstract 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 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.
Saraf Sharada、Kirby Charles、Kityamuweesi Taddeo、Lamers Susanna L.、Galiwango Ronald M.、Poon Art F. Y.、Redd Andrew D.、Hackman Jada、Gowanlock Sarah N.、Tomusange Stephen、Anok Aggrey、Ferreira Roux-Cil、Capoferri Adam A.、Miller Jernelle、Reynolds Steven J.、Lynch Briana、Quinn Thomas C.、Klock Ethan、Prodger Jessica L.、Martens Craig、Jamiru Samiri、Lai Jun、Brown Erin E.、Baker Owen、Rose Rebecca、Bruno Daniel、Buule Paul
Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDivision of Infectious Diseases, Johns Hopkins University School of MedicineRakai Health Sciences ProgramBioInfoExperts, LLCRakai Health Sciences ProgramDepartment of Pathology and Laboratory Medicine, Western University||Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western UniversityLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health||Division of Infectious Diseases, Johns Hopkins University School of Medicine||Institute of Infectious Disease and Molecular Medicine, University of Cape TownLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western UniversityRakai Health Sciences ProgramRakai Health Sciences ProgramDepartment of Pathology and Laboratory Medicine, Western UniversityDivision of Infectious Diseases, Johns Hopkins University School of MedicineDivision of Infectious Diseases, Johns Hopkins University School of MedicineLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health||Division of Infectious Diseases, Johns Hopkins University School of Medicine||Rakai Health Sciences ProgramLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health||Division of Infectious Diseases, Johns Hopkins University School of MedicineDivision of Infectious Diseases, Johns Hopkins University School of MedicineDepartment of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University||Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western UniversityGenomic Unit, Rocky Mountain Laboratories, NIAID, NIHRakai Health Sciences ProgramDivision of Infectious Diseases, Johns Hopkins University School of MedicineLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDivision of Infectious Diseases, Johns Hopkins University School of MedicineBioInfoExperts, LLCGenomic Unit, Rocky Mountain Laboratories, NIAID, NIHRakai Health Sciences Program
医学研究方法基础医学内科学
Saraf Sharada,Kirby Charles,Kityamuweesi Taddeo,Lamers Susanna L.,Galiwango Ronald M.,Poon Art F. Y.,Redd Andrew D.,Hackman Jada,Gowanlock Sarah N.,Tomusange Stephen,Anok Aggrey,Ferreira Roux-Cil,Capoferri Adam A.,Miller Jernelle,Reynolds Steven J.,Lynch Briana,Quinn Thomas C.,Klock Ethan,Prodger Jessica L.,Martens Craig,Jamiru Samiri,Lai Jun,Brown Erin E.,Baker Owen,Rose Rebecca,Bruno Daniel,Buule Paul.Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen[EB/OL].(2025-03-28)[2025-08-30].https://www.medrxiv.org/content/10.1101/2023.05.12.23289896.点此复制
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