title: Generation and mucosal transmissibility of emtricitabine- and tenofovir-resistant SHIV162P3 mutants in macaques.
abstract: Transmission of drug-resistant HIV has been widely documented. We generated tenofovir (TFV)- and emtricitabine (FTC)-resistant SHIV162P3 mutants that can be used to investigate the transmission efficiency of drug-resistant viruses and their impact on the efficacy of pre-exposure prophylaxis. Both SHIV162p3(M184V) and SHIV162p3(K65R) replicated in vitro at high titers. Drug resistance profiles were similar to those seen in HIV. Virus infectivity to virion particle ratios were 4- and 10-fold lower in SHIV162p3(M184V) and SHIV162p3(K65R), compared to a concurrently generated WT SHIV162p3, respectively. Mucosal transmissibility studies using a repeat low-dose macaque model of rectal and vaginal transmission showed that both mutants were able to efficiently infect macaques only after the dose was increased to adjust for fitness reductions due to K65R and M184V. Our results in limited number of macaques suggest that the reduction in fitness due to M184V and K65R decreases virus transmissibility, and identify in vitro infectivity parameters that associate with mucosal transmissibility.
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, USA.
authors.forename: Mian-er
authors.initials: ME
authors.lastname: Cong
authors.forename: Ae S
authors.initials: AS
authors.lastname: Youngpairoj
authors.forename: Wutyi
authors.initials: W
authors.lastname: Aung
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.forename: James
authors.initials: J
authors.lastname: Mitchell
authors.forename: Charles
authors.initials: C
authors.lastname: Dobard
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
authors.forename: J Gerardo
authors.initials: JG
authors.lastname: Garcia-Lerma
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D000068679:Emtricitabine; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D006801:Humans; D008251:Macaca; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology*; D011995:Recombination, Genetic; D016097:Simian Acquired Immunodeficiency Syndrome / Q000635:transmission* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D000068698:Tenofovir; D014776:Virus Cultivation
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine