In vivo evolution of env in SHIV-AD8 EO -infected rhesus macaques after AAV-vectored delivery of eCD4-Ig.

Autor: O'Hagan D; Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA., Shandilya S; Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA., Hopkins LJ; California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA., Hahn PA; Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA; The Skaggs Graduate School, The Scripps Research Institute, Jupiter, FL 33458, USA., Fuchs SP; University of Miami, Miller School of Medicine, Miami, FL 33136, USA., Martinez-Navio JM; University of Miami, Miller School of Medicine, Miami, FL 33136, USA., Alpert MD; Emmune Inc., Juno Beach, FL 33408, USA., Gardner MR; Department of Medicine, Emory University, Atlanta, GA 30322, USA., Desrosiers RC; University of Miami, Miller School of Medicine, Miami, FL 33136, USA., Gao G; Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA., Lifson JD; AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, MD 21702, USA., Farzan M; Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA., Ardeshir A; Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA., Martins MA; Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA. Electronic address: mauricio.martins@ufl.edu.
Jazyk: angličtina
Zdroj: Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Dec 12. Date of Electronic Publication: 2024 Dec 12.
DOI: 10.1016/j.ymthe.2024.12.015
Abstrakt: eCD4-immunoglobulin (Ig) is an HIV entry inhibitor that mimics the engagement of both CD4 and CCR5 with the HIV envelope (Env) protein, a property that imbues it with remarkable potency and breadth. However, env is exceptionally genetically malleable and can evolve to escape a wide variety of entry inhibitors. Here we document the evolution of partial eCD4-Ig resistance in SHIV-AD8 EO -infected rhesus macaques (RMs) treated with adeno-associated virus vectors encoding eCD4-Ig. In one RM, setpoint viremia plateaued at 1,000 vRNA copies/mL, despite concomitant serum concentrations of eCD4-Ig in the 60-110 μg/mL range, implying that the virus had gained partial eCD4-Ig resistance. Env mutations occurring prominently in this animal were cloned and further characterized. Three of these mutations (R315G, A436T, and G471E) were sufficient to confer substantial resistance to eCD4-Ig-mediated neutralization onto the parental Env, accompanied by a marked loss of viral fitness. This resistance was not driven by decreased CD4 affinity, subverted sulfopeptide mimicry, changes to co-receptor tropism, or by a gain of CD4 independence. Rather, our data argue that the Env evolving in this animal attained eCD4-Ig resistance by decreasing triggerability, stabilizing the triggered state, and changing the nature of its relationship to the host CD4.
Competing Interests: Declaration of interests M.A.M., M.D.A., M.R.G., and M.F. have significant financial interests in Emmune, Inc., a company that is developing HIV immunotherapies based on the immunoadhesin eCD4-Ig, and each serve in a consulting capacity for the company. These potential conflicts of interest are being managed by the authors’ respective institutions. None of the other authors or their immediate family members have any conflicts of interest to declare.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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