In vivo Serial Passaging of Human-Simian Immunodeficiency Virus Clones Identifies Characteristics for Persistent Viral Replication.

Autor: Thippeshappa R; Disease Intervention and Prevention Program, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States., Polacino P; Washington National Primate Research Center, University of Washington, Seattle, WA, United States., Chandrasekar SS; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States., Truong K; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States., Misra A; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States., Aulicino PC; Laboratorio de Biología Celular y Retrovirus, Hospital de Pediatría 'Juan P. Garrahan'-CONICET, Buenos Aires, Argentina., Hu SL; Washington National Primate Research Center, University of Washington, Seattle, WA, United States.; Department of Pharmaceutics, University of Washington, Seattle, WA, United States., Kaushal D; Host-Pathogen Interactions Program, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States., Kimata JT; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States.
Jazyk: angličtina
Zdroj: Frontiers in microbiology [Front Microbiol] 2021 Nov 18; Vol. 12, pp. 779460. Date of Electronic Publication: 2021 Nov 18 (Print Publication: 2021).
DOI: 10.3389/fmicb.2021.779460
Abstrakt: We previously reported that a human immunodeficiency virus type 1 with a simian immunodeficiency virus vif substitution (HSIV-vif NL4-3 ) could replicate in pigtailed macaques (PTMs), demonstrating that Vif is a species-specific tropism factor of primate lentiviruses. However, infections did not result in high-peak viremia or setpoint plasma viral loads, as observed during simian immunodeficiency virus (SIV) infection of PTMs. Here, we characterized variants isolated from one of the original infected animals with CD4 depletion after nearly 4years of infection to identify determinants of increased replication fitness. In our studies, we found that the HSIV-vif clones did not express the HIV-1 Vpr protein due to interference from the vpx open reading frame (ORF) in singly spliced vpr mRNA. To examine whether these viral genes contribute to persistent viral replication, we generated infectious HSIV-vif clones expressing either the HIV-1 Vpr or SIV Vpx protein. And then to determine viral fitness determinants of HSIV-vif, we conducted three rounds of serial in vivo passaging in PTMs, starting with an initial inoculum containing a mixture of CXCR4-tropic [Vpr-HSIV-vif NL4-3 isolated at 196 (C/196) and 200 (C/200) weeks post-infection from a PTM with depressed CD4 counts] and CCR5-tropic HSIV (Vpr + HSIV-vif derivatives based NL-AD8 and Bru-Yu2 and a Vpx expressing HSIV-vif Yu2 ). Interestingly, all infected PTMs showed peak plasma viremia close to or above 10 5 copies/ml and persistent viral replication for more than 20weeks. Infectious molecular clones (IMCs) recovered from the passage 3 PTM (HSIV-P3 IMCs) included mutations required for HIV-1 Vpr expression and those mutations encoded by the CXCR4-tropic HSIV-vif NL4-3 isolate C/196. The data indicate that the viruses selected during long-term infection acquired HIV-1 Vpr expression, suggesting the importance of Vpr for in vivo pathogenesis. Further passaging of HSIV-P3 IMCs in vivo may generate pathogenic variants with higher replication capacity, which will be a valuable resource as challenge virus in vaccine and cure studies.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Thippeshappa, Polacino, Chandrasekar, Truong, Misra, Aulicino, Hu, Kaushal and Kimata.)
Databáze: MEDLINE
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