title: Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques.
abstract: Mucosal surfaces are vulnerable to human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection and thus are key sites for eliciting vaccine-mediated protection. Vaccine protocols carried out at the Yerkes Primate Research Center utilized SIVmac239-based immunization strategies with intrarectal and intravaginal SIVsmE660 challenge of rhesus macaques. We investigated whether there were genetic signatures associated with SIVsmE660 intrarectal and intravaginal transmissions in vaccinated and unvaccinated monkeys. When transmitted/founder (T/F) envelope (Env) sequences from 49 vaccinated and 15 unvaccinated macaques were compared to each other, we were unable to identify any vaccine breakthrough signatures. In contrast, when the vaccinated and control T/F Envs were combined and compared to the challenge stock, residues at gp120 positions 23, 45, 47, and 70 (Ile-Ala-Lys-Asn [I-A-K-N]) emerged as signatures of mucosal transmission. However, T/F Envs derived from intrarectal and intravaginal infections were not different. Our data suggest that the vaginal and rectal mucosal environments both imposed a strong selection bias for SIVsmE660 variants carrying I-A-K-N that was not further enhanced by immunization. These findings, combined with the strong conservation of A-K-N in most HIV-2/SIVsmm isolates and the analogous residues in HIV-1/SIVcpz isolates, suggest that these residues confer increased transmission fitness to SIVsmE660.
  
  
  OBJECTIVE
  Most HIV-1 infections occur across a mucosal barrier, and it is therefore important to understand why these sites are vulnerable and how to protect them with a vaccine. To gain insight into these questions, we studied rhesus macaques that were vaccinated with SIVmac239 and unvaccinated controls to determine whether the SIVsmE660 viral variants that infected these two groups were different. We did not find differences between viral variants in the absence versus presence of vaccination-induced immunity, but we did find that the SIVsmE660 viral variants that infected the monkeys, regardless of vaccination, were different from the dominant population found in the viral challenge inoculum. Our data suggest that the mucosal environments of the vagina and rectum both impose a strong selection for the SIVsmE660 variants in the challenge inoculum that are most like SIV and HIVs that circulate in nature.
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
authors.forename: S Abigail
authors.initials: SA
authors.lastname: Smith
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Kilgore
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Sudhir Pai
authors.initials: SP
authors.lastname: Kasturi
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA.
authors.forename: Rama R
authors.initials: RR
authors.lastname: Amara
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA cderdey@emory.edu.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
mesh_terms: D000818:Animals; D018562:Disease Transmission, Infectious; D007413:Intestinal Mucosa / Q000276:immunology / Q000821:virology; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000635:transmission* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; C069623:gp120 protein, Simian immunodeficiency virus