title: Prime-boost vaccination with heterologous live vectors encoding SIV gag and multimeric HIV-1 gp160 protein: efficacy against repeated mucosal R5 clade C SHIV challenges.
abstract: We sought to induce primate immunodeficiency virus-specific cellular and neutralizing antibody (nAb) responses in rhesus macaques (RM) through a bimodal vaccine approach. RM were immunized intragastrically (i.g.) with the live-attenuated Listeria monocytogenes (Lm) vector Lmdd-BdopSIVgag encoding SIVmac239 gag. SIV Gag-specific cellular responses were boosted by intranasal and intratracheal administration of replication-competent adenovirus (Ad5hr-SIVgag) encoding the same gag. To broaden antiviral immunity, the RM were immunized with multimeric HIV clade C (HIV-C) gp160 and HIV Tat. SIV Gag-specific cellular immune responses and HIV-1 nAb developed in some RM. The animals were challenged intrarectally with five low doses of R5 SHIV-1157ipEL-p, encoding a heterologous HIV-C Env (22.1% divergent to the Env immunogen). All five controls became viremic. One out of ten vaccinees was completely protected and another had low peak viremia. Sera from the completely and partially protected RM neutralized the challenge virus > 90%; these RM also had strong SIV Gag-specific proliferation of CD8⁺ T cells. Peak and area under the curve of plasma viremia (during acute phase) among vaccinees was lower than for controls, but did not attain significance. The completely protected RM showed persistently low numbers of the α4β7-expressing CD4⁺ T cells; the latter have been implicated as preferential virus targets in vivo. Thus, vaccine-induced immune responses and relatively lower numbers of potential target cells were associated with protection.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Samir K
authors.initials: SK
authors.lastname: Lakhashe
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Velu
authors.forename: Gaia
authors.initials: G
authors.lastname: Sciaranghella
authors.forename: Nagadenahalli B
authors.initials: NB
authors.lastname: Siddappa
authors.forename: Janet M
authors.initials: JM
authors.lastname: Dipasquale
authors.forename: Girish
authors.initials: G
authors.lastname: Hemashettar
authors.forename: John K
authors.initials: JK
authors.lastname: Yoon
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rasmussen
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Lee
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Novembre
authors.forename: François
authors.initials: F
authors.lastname: Villinger
authors.forename: Rama Rao
authors.initials: RR
authors.lastname: Amara
authors.forename: Maria
authors.initials: M
authors.lastname: Kahn
authors.forename: Shiu-Lok
authors.initials: SL
authors.lastname: Hu
authors.forename: Sufen
authors.initials: S
authors.lastname: Li
authors.forename: Zhongxia
authors.initials: Z
authors.lastname: Li
authors.forename: Fred R
authors.initials: FR
authors.lastname: Frankel
authors.forename: Marjorie
authors.initials: M
authors.lastname: Robert-Guroff
authors.forename: Welkin E
authors.initials: WE
authors.lastname: Johnson
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Ruprecht
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D058501:Enzyme-Linked Immunospot Assay; D015683:Gene Products, gag / Q000008:administration & dosage / Q000276:immunology*; D019302:HIV Envelope Protein gp160 / Q000008:administration & dosage / Q000276:immunology*; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology; D018928:Immunity, Mucosal; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000032:analysis; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D014611:Vaccination; D019562:Viral Load; D014766:Viremia / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; C066594:Gag protein p27, Simian immunodeficiency virus; D015683:Gene Products, gag; D019302:HIV Envelope Protein gp160; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma