New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention, and Cure
Hui Li, Shuyi Wang, Fang-Hua Lee, Ryan S. Roark, Alex I. Murphy, Jessica G. Smith, Chengyan Zhao, Juliette Rando, Neha Chohan, Yu Ding, Eunlim Kim, Emily Lindemuth, Katharine J. Bar, Ivona Pandrea, Cristian Apetrei, Brandon F. Keele, Jeffrey D. Lifson, Mark G. Lewis, Thomas N. Denny, Barton F. Haynes, Beatrice H. Hahn, George M. Shaw
Abstract
SHIV infection of Indian rhesus macaques is an important animal model for studying HIV-1 transmission, prevention, immunopathogenesis and cure. Such research is timely, given recent progress with active and passive immunization and novel approaches to HIV-1 cure. Given the multifaceted roles of HIV-1 Env in cell tropism and virus entry, and as a target for neutralizing and non-neutralizing antibodies, Envs selected for SHIV construction are of paramount importance. Until recently, it has been impossible to strategically design SHIVs bearing clinically relevant Envs that replicate consistently in monkeys. This changed with the discovery that bulky aromatic substitutions at residue Env375 confer enhanced affinity to rhesus CD4. Here, we show that 10 new SHIVs bearing primary HIV-1 Envs with residue 375 substitutions replicated efficiently in RMs and could be transmitted efficiently across rectal, vaginal, penile and oral mucosa. These findings suggest an expanded role for SHIVs as a model of HIV-1 infection.