Adaptation of a transmitted/founder simian-human immunodeficiency virus for enhanced replication in rhesus macaques.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
10
12
2022
accepted:
21
06
2023
revised:
14
07
2023
medline:
17
7
2023
pubmed:
3
7
2023
entrez:
3
7
2023
Statut:
epublish
Résumé
Transmitted/founder (TF) simian-human immunodeficiency viruses (SHIVs) express HIV-1 envelopes modified at position 375 to efficiently infect rhesus macaques while preserving authentic HIV-1 Env biology. SHIV.C.CH505 is an extensively characterized virus encoding the TF HIV-1 Env CH505 mutated at position 375 shown to recapitulate key features of HIV-1 immunobiology, including CCR5-tropism, a tier 2 neutralization profile, reproducible early viral kinetics, and authentic immune responses. SHIV.C.CH505 is used frequently in nonhuman primate studies of HIV, but viral loads after months of infection are variable and typically lower than those in people living with HIV. We hypothesized that additional mutations besides Δ375 might further enhance virus fitness without compromising essential components of CH505 Env biology. From sequence analysis of SHIV.C.CH505-infected macaques across multiple experiments, we identified a signature of envelope mutations associated with higher viremia. We then used short-term in vivo mutational selection and competition to identify a minimally adapted SHIV.C.CH505 with just five amino acid changes that substantially improve virus replication fitness in macaques. Next, we validated the performance of the adapted SHIV in vitro and in vivo and identified the mechanistic contributions of selected mutations. In vitro, the adapted SHIV shows improved virus entry, enhanced replication on primary rhesus cells, and preserved neutralization profiles. In vivo, the minimally adapted virus rapidly outcompetes the parental SHIV with an estimated growth advantage of 0.14 days-1 and persists through suppressive antiretroviral therapy to rebound at treatment interruption. Here, we report the successful generation of a well-characterized, minimally adapted virus, termed SHIV.C.CH505.v2, with enhanced replication fitness and preserved native Env properties that can serve as a new reagent for NHP studies of HIV-1 transmission, pathogenesis, and cure.
Identifiants
pubmed: 37399208
doi: 10.1371/journal.ppat.1011059
pii: PPATHOGENS-D-22-02143
pmc: PMC10348547
doi:
Substances chimiques
env Gene Products, Human Immunodeficiency Virus
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1011059Subventions
Organisme : NIAID NIH HHS
ID : UM1 AI126619
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI164570
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI131722
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI162646
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI131338
Pays : United States
Informations de copyright
Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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