ALVAC-SIV- gag - pol - env -Based Vaccination and Macaque Major Histocompatibility Complex Class I (A*01) Delay Simian Immunodeficiency Virus SIV mac -Induced Immunodeficiency

Abstract

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 SIV mac251 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 SIV mac251 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.