Neutralization-Sensitive R5 SHIV-2873Nip Encoding env from a Infant with Recent HIV Clade C Infection

Authors

• Nagadenahalli B. Siddappa, Dana-Farber Cancer Institute
• Ruijiang Song, Harvard Medical School
• Victor G. Kramer, Dana-Farber Cancer Institute
• Agnes-Laurence Chenine, Dana-Farber Cancer Institute
• Vijayakumar Velu, Division of Microbiology and Immunology, Yerkes National Primate Research Center
• Helena Ong, Dana-Farber Cancer Institute
• Robert A. Rasmussen, Dana-Farber Cancer Institute
• Ricky D. Grisson, Dana-Farber Cancer Institute
• Charles Wood, University of Nebraska-LincolnFollow
• Hong Zhang, Univesity of Nebraska - LincolnFollow
• Chipepo Kankasa, University Teaching Hospital, Lusaka, Zambia,
• Rama Rao Amara, Division of Microbiology and Immunology, Yerkes National Primate Research Center
• James G. Else, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia
• Francis J. Novembre, Division of Microbiology and Immunology, Yerkes National Primate Research Center
• David Montefiori, Department of Surgery, Duke University Medical Center, Durham, North Carolina
• Ruth M. Ruprecht, Harvard Medical School

Document Type

Article

Date of this Version

11-19-2008

Comments

JVI Accepts, published online ahead of print on 19 November 2008 Published in J. Virol. doi:10.1128/JVI.02066-08 Copyright © 2008, American Society for Microbiology and/or the Listed Authors/Institutions. Used by permission.

Abstract

HIV-C (HIV-C) accounts for >56% of all HIV infections worldwide. To investigate vaccine safety and efficacy in non-human primates, a pathogenic, R5-tropic, neutralization sensitive simian-human immunodeficiency virus (SHIV) encoding HIV-C env would be desirable. We have constructed SHIV-2873Ni, an R5 SHIV encoding a primary pediatric HIV-C env isolated from a 2-month old Zambian infant, who progressed to death within one year of birth. SHIV-2873Ni was constructed using SHIV-1157ipd3N4 (Song et al., J. Viol. 80:8729-38, 2006) as backbone since the latter contains additional NF-κB sites in the long terminal repeats (LTRs) to enhance viral replicative capacity. The parental virus, SHIV-2873Ni, was serially passaged through 5 rhesus monkeys (RM); SHIV-2873Nip, the resulting passaged virus, was reisolated from the 4th recipient about 1 year post inoculation. SHIV-2873Nip was replication-competent in RM peripheral blood mononuclear cells (PBMC) of all random donors tested, was exclusively R5 tropic and its env gene clustered with HIV-C by phylogenetic analysis; its high sensitivity to neutralization led to a classification as Tier 1 virus. Indian-origin RM were inoculated by different mucosal routes, resulting in high peak viral RNA loads. Signs of virus-induced disease include depletion of gut CD4⁺ T lymphocytes, loss of memory T cells in blood, and thrombocytopenia that resulted in fatal cerebral hemorrhage. SHIV-2873Nip is a highly replication-competent, mucosally transmissible, pathogenic R5 virus that will be useful to study viral pathogenesis and to assess the efficacy of immunogens targeting HIV-C Env.