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Title: Novel strategy to adapt simian-human immunodeficiency virus e1 carrying env from an rv144 volunteer to rhesus macaques: Coreceptor switch and final recovery of a pathogenic virus with exclusive r5 tropism
Authors: Hanna B. Scinto
Sandeep Gupta
Swati Thorat
Muhammad M. Mukhtar
Anthony Griffiths
Jennifer Delgado
Elizabeth Plake
Hemant K. Vyas
Amanda Strickland
Siddappa N. Byrareddy
David C. Montefiori
Celia LaBranche
Ranajit Pal
Jim Treece
Sharon Orndorff
Maria Grazia Ferrari
Deborah Weiss
Agnes Laurence Chenine
Robert McLinden
Nelson Michael
Jerome H. Kim
Merlin L. Robb
Supachai Rerks-Ngarm
Punnee Pitisuttithum
Sorachai Nitayaphan
Ruth M. Ruprecht
Duke University Medical Center
Advanced BioScience Laboratories, Inc.
International Vaccine Institute, Seoul
Texas Biomedical Research Institute
University of Texas Health Science Center at San Antonio
University of Nebraska Medical Center
Armed Forces Research Institute of Medical Sciences, Thailand
Thailand Ministry of Public Health
Dana-Farber Cancer Institute
Mahidol University
Harvard Medical School
Keywords: Agricultural and Biological Sciences;Immunology and Microbiology
Issue Date: 1-Jul-2018
Citation: Journal of Virology. Vol.92, No.14 (2018)
Abstract: ©2018 American Society for Microbiology. The phase III RV144 human immunodeficiency virus (HIV) vaccine trial conducted in Thailand remains the only study to show efficacy in decreasing the HIV acquisition risk. In Thailand, circulating recombinant forms of HIV clade A/E (CRF01_AE) predominate; in such viruses, env originates from clade E (HIV-E). We constructed a simian-human immunodeficiency virus (SHIV) chimera carrying env isolated from an RV144 placebo recipient in the SHIV-1157ipd3N4 backbone. The latter contains long terminal repeats (LTRs) with duplicated NF-B sites, thus resembling HIV LTRs. We devised a novel strategy to adapt the parental infectious molecular clone (IMC), R5 SHIV-E1, to rhesus macaques: the simultaneous depletion of B and CD8 cells followed by the intramuscular inoculation of proviral DNA and repeated administrations of cell-free virus. High-level viremia and CD4 T-cell depletion ensued. Passage 3 virus unexpectedly caused acute, irreversible CD4 T-cell loss; the partially adapted SHIV had become dual tropic. Virus and IMCs with exclusive R5 tropism were reisolated from earlier passages, combined, and used to complete adaptation through additional macaques. The final isolate, SHIV-E1p5, remained solely R5 tropic. It had a tier 2 neutralization phenotype, was mucosally transmissible, and was pathogenic. Deep sequencing revealed 99% Env amino acid sequence conservation; X4-only and dual-tropic strains had evolved independently from an early branch of parental SHIV-E1. To conclude, our primate model data reveal that SHIV-E1p5 recapitulates important aspects of HIV transmission and pathobiology in humans.
ISSN: 10985514
Appears in Collections:Scopus 2018

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