Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimenResearch in context
Roux-Cil Ferreira,
Steven J. Reynolds,
Adam A. Capoferri,
Owen R. Baker,
Erin E. Brown,
Ethan Klock,
Jernelle Miller,
Jun Lai,
Sharada Saraf,
Charles Kirby,
Briana Lynch,
Jada Hackman,
Sarah N. Gowanlock,
Stephen Tomusange,
Samiri Jamiru,
Aggrey Anok,
Taddeo Kityamuweesi,
Paul Buule,
Daniel Bruno,
Craig Martens,
Rebecca Rose,
Susanna L. Lamers,
Ronald M. Galiwango,
Art F.Y. Poon,
Thomas C. Quinn,
Jessica L. Prodger,
Andrew D. Redd
Affiliations
Roux-Cil Ferreira
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
Steven J. Reynolds
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
Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Owen R. Baker
Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Erin E. Brown
Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Ethan Klock
Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jernelle Miller
Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jun Lai
Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Sharada Saraf
Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Charles Kirby
Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Briana Lynch
Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Jada Hackman
Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Sarah N. Gowanlock
Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
Stephen Tomusange
Rakai Health Sciences Program, Kalisizo, Uganda
Samiri Jamiru
Rakai Health Sciences Program, Kalisizo, Uganda
Aggrey Anok
Rakai Health Sciences Program, Kalisizo, Uganda
Taddeo Kityamuweesi
Rakai Health Sciences Program, Kalisizo, Uganda
Paul Buule
Rakai Health Sciences Program, Kalisizo, Uganda
Daniel Bruno
Genomics Research Section, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA
Craig Martens
Genomics Research Section, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA
Rebecca Rose
BioInfoExperts, LLC, Thibodaux, LA, USA
Susanna L. Lamers
BioInfoExperts, LLC, Thibodaux, LA, USA
Ronald M. Galiwango
Rakai Health Sciences Program, Kalisizo, Uganda
Art F.Y. Poon
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
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
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
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; Corresponding author. Johns Hopkins University, Rangos Building Room 540, 851 N Wolfe St, Baltimore, MD 21205, USA.
Summary: 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: 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: 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: 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: 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.
