title: Protection of macaques with diverse MHC genotypes against a heterologous SIV by vaccination with a deglycosylated live-attenuated SIV.
abstract: HIV vaccine development has been hampered by issues such as undefined correlates of protection and extensive diversity of HIV. We addressed these issues using a previously established SIV-macaque model in which SIV mutants with deletions of multiple gp120 N-glycans function as potent live attenuated vaccines to induce near-sterile immunity against the parental pathogenic SIVmac239. In this study, we investigated the protective efficacy of these mutants against a highly pathogenic heterologous SIVsmE543-3 delivered intravenously to rhesus macaques with diverse MHC genotypes. All 11 vaccinated macaques contained the acute-phase infection with blood viral loads below the level of detection between 4 and 10 weeks postchallenge (pc), following a transient but marginal peak of viral replication at 2 weeks in only half of the challenged animals. In the chronic phase, seven vaccinees contained viral replication for over 80 weeks pc, while four did not. Neutralizing antibodies against challenge virus were not detected. Although overall levels of SIV specific T cell responses did not correlate with containment of acute and chronic viral replication, a critical role of cellular responses in the containment of viral replication was suggested. Emergence of viruses with altered fitness due to recombination between the vaccine and challenge viruses and increased gp120 glycosylation was linked to the failure to control SIV. These results demonstrate the induction of effective protective immune responses in a significant number of animals against heterologous virus by infection with deglycosylated attenuated SIV mutants in macaques with highly diverse MHC background. These findings suggest that broad HIV cross clade protection is possible, even in hosts with diverse genetic backgrounds. In summary, results of this study indicate that deglycosylated live-attenuated vaccines may provide a platform for the elucidation of correlates of protection needed for a successful HIV vaccine against diverse isolates.
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Sugimoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.forename: Taeko
authors.initials: T
authors.lastname: Naruse
authors.forename: Eiji
authors.initials: E
authors.lastname: Kajiwara
authors.forename: Teiichiro
authors.initials: T
authors.lastname: Shiino
authors.forename: Natsuko
authors.initials: N
authors.lastname: Umano
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ueda
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Sato
authors.forename: Shinji
authors.initials: S
authors.lastname: Ohgimoto
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hirsch
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyazawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nagai
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Mori
mesh_terms: D000818:Animals; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006031:Glycosylation; D008253:Macaca mulatta; D017354:Point Mutation / Q000235:genetics; D018449:SAIDS Vaccines / Q000737:chemistry / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D018449:SAIDS Vaccines; D014613:Vaccines, Attenuated