Pathogenic infection of Rhesus macaques by an evolving SIV-HIV derived from CCR5-using envelope genes of acute HIV-1 infections

• Published in: Virology (New York, N.Y.) N.Y.), 2016-12, Vol.499, p.298-312
• Main Authors: Asmal, Mohammed, Lane, Sophie, Tian, Meijuan, Nickel, Gabrielle, Venner, Colin, Dirk, Brennan, Dikeakos, Jimmy, Luedemann, Corinne, Mach, Linh, Balachandran, Harikrishnan, Buzby, Adam, Rao, Srinivas, Letvin, Norman, Gao, Yong, Arts, Eric J
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies, Viral - immunology; Disease Models, Animal; Envelope; Evolution, Molecular; Gene Products, env - chemistry; Gene Products, env - genetics; Gene Products, env - immunology; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - genetics; HIV Envelope Protein gp120 - immunology; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - virology; HIV-1 - classification; HIV-1 - genetics; HIV-1 - immunology; HIV-1 - pathogenicity; Humans; Immunity, Humoral; Infectious Disease; Macaca mulatta; Molecular Sequence Data; Mutation, Missense; Pathogenesis; Phylogeny; Receptors, CCR5 - genetics; Receptors, CCR5 - immunology; Receptors, Virus - genetics; Receptors, Virus - immunology; Rhesus macaque; Sequence Alignment; Simian Immunodeficiency Virus - classification; Simian Immunodeficiency Virus - genetics; Simian Immunodeficiency Virus - immunology; Simian Immunodeficiency Virus - pathogenicity; SIV-HIV chimeric viruses; Virulence
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2016.09.021

Abstract For studies on vaccines and therapies for HIV disease, SIV-HIV chimeric viruses harboring the HIV-1 env gene (SHIVenv) remain the best virus in non-human primate models. However, there are still very few SHIVenv viruses that can cause AIDS in non-CD8-depleted animals. In the present study, a recently created CCR5-using SHIVenv_B3 virus with env gene derived from acute/early HIV-1 infections (AHI) successfully established pathogenic infection in macaques. Through a series of investigations on the evolution, mutational profile, and phenotype of the virus and the resultant humoral immune response in infected rhesus macaques, we found that the E32K mutation in the Env C1 domain was associated with macaque pathogenesis, and that the electrostatic interactions in Env may favor E32K at the gp120 N terminus and “lock” the binding to heptad repeat 1 of gp41 in the trimer and produce a SHIVenv with increased fitness and pathogenesis during macaque infections.