ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency

T-cell-mediated immune effector mechanisms play an important role in the co ntainment of human immunodeficiency virus/simian immunodeficiency virus (HI V/SIV) replication after infection. Both vaccination- and infection-induced T-cell responses are dependent on the host major histocompatibility comple x classes I and II (MHC-I and MHC-II) antigens. Here we report that both in herent, host-dependent immune responses to SIVmac251 infection and vaccinat ion-induced immune responses to viral antigens were able to reduce virus re plication 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 duri ng primary infection, preservation of CD4(+) T cells, and delayed disease p rogression following ;intrarectal challenge exposure of the animals to SIVm ac251 ((561)). ALVAC-SIV-gpe immunization induced cytotoxic T-lymphocyte (C TL) responses cumulatively in 67% of the immunized animals. Following viral challenge, a significant secondary virus-specific CD8(+) T-cell response w as observed in the vaccinated macaques. In the same immunized macaques, a d ecrease 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 o f the vaccinated macaques was also observed. Neither boosting the ALVAC-SIV -gpe with gp120 immunizations nor administering the vaccine by the combinat ion of mucosal and systemic immunization routes increased significantly the protective effect of the ALVAC-SIV-gpe vaccine. While assessing the role o f MHC-I Mamu-A*01 alone in the restriction of viremia following challenge o f nonvaccinated animals with other SIV isolates, we observed that the virus load was not significantly lower in MamuA*01-positive macaques following i ntravenous challenge with either SIVmac251 (561) or SIVSME660. However, a s ignificant delay in CD4(+) T-cell loss was observed in Mamu-A*01-positive m acaques in each group. Of interest, in the case of intravenous or intrarect al challenge with the chimeric SIV/HIV strains SHIV89.6P or SHIVKU2, respec tively, MHC-I Mamu-A*01-positive macaques did not significantly restrict pr imary viremia. The finding of the protective effect of the Mamu-A*01 molecu le parallels the protective effect of the B*5701 HLA allele in HIV-1-infect ed humans and needs to be accounted for in the evaluation of vaccine effica cy against SIV challenge models.