Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen.

Dolutegravir HIV Integrase inhibitor Latent reservoir Uganda

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
04 Mar 2024
Historique:
received: 24 08 2023
revised: 16 02 2024
accepted: 16 02 2024
medline: 15 3 2024
pubmed: 15 3 2024
entrez: 14 3 2024
Statut: aheadofprint

Résumé

The principal barrier to an HIV cure is the presence of the latent viral reservoir (LVR), which has been understudied in African populations. From 2018 to 2019, Uganda instituted a nationwide rollout of ART consisting of Dolutegravir (DTG) with two NRTI, which replaced the previous regimen of one NNRTI and the same two NRTI. Changes in the inducible replication-competent LVR (RC-LVR) of ART-suppressed Ugandans with HIV (n = 88) from 2015 to 2020 were examined using the quantitative viral outgrowth assay. Outgrowth viruses were examined for viral evolution. Changes in the RC-LVR were analyzed using three versions of a Bayesian model that estimated the decay rate over time as a single, linear rate (model A), or allowing for a change at time of DTG initiation (model B&C). Model A estimated the slope of RC-LVR change as a non-significant positive increase, which was due to a temporary spike in the RC-LVR that occurred 0-12 months post-DTG initiation (p < 0.005). This was confirmed with models B and C; for instance, model B estimated a significant decay pre-DTG initiation with a half-life of 6.9 years, and an ∼1.7-fold increase in the size of the RC-LVR post-DTG initiation. There was no evidence of viral failure or consistent evolution in the cohort. These data suggest that the change from NNRTI- to DTG-based ART is associated with a significant temporary increase in the circulating RC-LVR. Supported by the NIH (grant 1-UM1AI164565); Gilead HIV Cure Grants Program (90072171); Canadian Institutes of Health Research (PJT-155990); and Ontario Genomics-Canadian Statistical Sciences Institute.

Sections du résumé

BACKGROUND BACKGROUND
The principal barrier to an HIV cure is the presence of the latent viral reservoir (LVR), which has been understudied in African populations. From 2018 to 2019, Uganda instituted a nationwide rollout of ART consisting of Dolutegravir (DTG) with two NRTI, which replaced the previous regimen of one NNRTI and the same two NRTI.
METHODS METHODS
Changes in the inducible replication-competent LVR (RC-LVR) of ART-suppressed Ugandans with HIV (n = 88) from 2015 to 2020 were examined using the quantitative viral outgrowth assay. Outgrowth viruses were examined for viral evolution. Changes in the RC-LVR were analyzed using three versions of a Bayesian model that estimated the decay rate over time as a single, linear rate (model A), or allowing for a change at time of DTG initiation (model B&C).
FINDINGS RESULTS
Model A estimated the slope of RC-LVR change as a non-significant positive increase, which was due to a temporary spike in the RC-LVR that occurred 0-12 months post-DTG initiation (p < 0.005). This was confirmed with models B and C; for instance, model B estimated a significant decay pre-DTG initiation with a half-life of 6.9 years, and an ∼1.7-fold increase in the size of the RC-LVR post-DTG initiation. There was no evidence of viral failure or consistent evolution in the cohort.
INTERPRETATION CONCLUSIONS
These data suggest that the change from NNRTI- to DTG-based ART is associated with a significant temporary increase in the circulating RC-LVR.
FUNDING BACKGROUND
Supported by the NIH (grant 1-UM1AI164565); Gilead HIV Cure Grants Program (90072171); Canadian Institutes of Health Research (PJT-155990); and Ontario Genomics-Canadian Statistical Sciences Institute.

Identifiants

DOI: 10.1016/j.ebiom.2024.105040 PMID: 38485563
pubmed: 38485563
pii: S2352-3964(24)00075-6
doi: 10.1016/j.ebiom.2024.105040
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

105040

Informations de copyright

Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of interests RR and SLL are employed by BioInfoExperts, LLC. No other authors have any conflicts to report.

Auteurs

Roux-Cil Ferreira (RC)

Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Steven J Reynolds (SJ)

Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Rakai Health Sciences Program, Kalisizo, Uganda.

Adam A Capoferri (AA)

Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Owen R Baker (OR)

Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Erin E Brown (EE)

Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Ethan Klock (E)

Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Jernelle Miller (J)

Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Jun Lai (J)

Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Sharada Saraf (S)

Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Charles Kirby (C)

Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Briana Lynch (B)

Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Jada Hackman (J)

Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Sarah N Gowanlock (SN)

Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

Stephen Tomusange (S)

Rakai Health Sciences Program, Kalisizo, Uganda.

Samiri Jamiru (S)

Rakai Health Sciences Program, Kalisizo, Uganda.

Aggrey Anok (A)

Rakai Health Sciences Program, Kalisizo, Uganda.

Taddeo Kityamuweesi (T)

Rakai Health Sciences Program, Kalisizo, Uganda.

Paul Buule (P)

Rakai Health Sciences Program, Kalisizo, Uganda.

Daniel Bruno (D)

Genomics Research Section, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA.

Craig Martens (C)

Genomics Research Section, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA.

Rebecca Rose (R)

BioInfoExperts, LLC, Thibodaux, LA, USA.

Susanna L Lamers (SL)

BioInfoExperts, LLC, Thibodaux, LA, USA.

Ronald M Galiwango (RM)

Rakai Health Sciences Program, Kalisizo, Uganda.

Art F Y Poon (AFY)

Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

Thomas C Quinn (TC)

Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Jessica L Prodger (JL)

Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

Andrew D Redd (AD)

Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. Electronic address: reddandrew@niaid.nih.gov.

Classifications MeSH