title: ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency.
abstract: T-cell-mediated immune effector mechanisms play an important role in the containment of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication after infection. Both vaccination- and infection-induced T-cell responses are dependent on the host major histocompatibility complex classes I and II (MHC-I and MHC-II) antigens. Here we report that both inherent, host-dependent immune responses to SIVmac251 infection and vaccination-induced immune responses to viral antigens were able to reduce virus replication and/or CD4+ T-cell loss. Both the presence of the MHC-I Mamu-A*01 genotype and vaccination of rhesus macaques with ALVAC-SIV-gag-pol-env (ALVAC-SIV-gpe) contributed to the restriction of SIVmac251 replication during primary infection, preservation of CD4+ T cells, and delayed disease progression following intrarectal challenge exposure of the animals to SIV(mac251 (561)). ALVAC-SIV-gpe immunization induced cytotoxic T-lymphocyte (CTL) responses cumulatively in 67% of the immunized animals. Following viral challenge, a significant secondary virus-specific CD8+ T-cell response was observed in the vaccinated macaques. In the same immunized macaques, a decrease in virus load during primary infection (P = 0.0078) and protection from CD4 loss during both acute and chronic phases of infection (P = 0.0099 and P = 0.03, respectively) were observed. A trend for enhanced survival of the vaccinated macaques was also observed. Neither boosting the ALVAC-SIV-gpe with gp120 immunizations nor administering the vaccine by the combination of mucosal and systemic immunization routes increased significantly the protective effect of the ALVAC-SIV-gpe vaccine. While assessing the role of MHC-I Mamu-A*01 alone in the restriction of viremia following challenge of nonvaccinated animals with other SIV isolates, we observed that the virus load was not significantly lower in Mamu-A*01-positive macaques following intravenous challenge with either SIV(mac251 (561)) or SIV(SME660). However, a significant delay in CD4+ T-cell loss was observed in Mamu-A*01-positive macaques in each group. Of interest, in the case of intravenous or intrarectal challenge with the chimeric SIV/HIV strains SHIV(89.6P) or SHIV(KU2), respectively, MHC-I Mamu-A*01-positive macaques did not significantly restrict primary viremia. The finding of the protective effect of the Mamu-A*01 molecule parallels the protective effect of the B*5701 HLA allele in HIV-1-infected humans and needs to be accounted for in the evaluation of vaccine efficacy against SIV challenge models.
authors.affiliation: Advanced BioScience Laboratories, Inc., Kensington, Maryland 20895, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pal
authors.forename: D
authors.initials: D
authors.lastname: Venzon
authors.forename: N L
authors.initials: NL
authors.lastname: Letvin
authors.forename: S
authors.initials: S
authors.lastname: Santra
authors.forename: D C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: N R
authors.initials: NR
authors.lastname: Miller
authors.forename: E
authors.initials: E
authors.lastname: Tryniszewska
authors.forename: M G
authors.initials: MG
authors.lastname: Lewis
authors.forename: T C
authors.initials: TC
authors.lastname: VanCott
authors.forename: V
authors.initials: V
authors.lastname: Hirsch
authors.forename: R
authors.initials: R
authors.lastname: Woodward
authors.forename: A
authors.initials: A
authors.lastname: Gibson
authors.forename: M
authors.initials: M
authors.lastname: Grace
authors.forename: E
authors.initials: E
authors.lastname: Dobratz
authors.forename: P D
authors.initials: PD
authors.lastname: Markham
authors.forename: Z
authors.initials: Z
authors.lastname: Hel
authors.forename: J
authors.initials: J
authors.lastname: Nacsa
authors.forename: M
authors.initials: M
authors.lastname: Klein
authors.forename: J
authors.initials: J
authors.lastname: Tartaglia
authors.forename: G
authors.initials: G
authors.lastname: Franchini
mesh_terms: D000818:Animals; D015686:Gene Products, env / Q000008:administration & dosage* / Q000276:immunology; D015683:Gene Products, gag / Q000008:administration & dosage* / Q000276:immunology; D015684:Gene Products, pol / Q000008:administration & dosage* / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D008251:Macaca; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014611:Vaccination; D014616:Vaccinia virus; D014765:Viral Vaccines / Q000008:administration & dosage* / Q000276:immunology
chemical_list: C078788:ALVAC vaccine; D015686:Gene Products, env; D015683:Gene Products, gag; D015684:Gene Products, pol; D015395:Histocompatibility Antigens Class I; D014765:Viral Vaccines