Haga T, Kuwata T, Ui M, Igarashi T, Miyazaki Y, Hayami M
Laboratory of Pathogenic Virus, Institute for Virus Research, Kyoto University, Japan.
Microbiol Immunol. 1998;42(4):245-51. doi: 10.1111/j.1348-0421.1998.tb02279.x.
The lack of a suitable animal model is a major obstacle to developing anti-HIV-1 vaccines. We successfully generated an SIVmac/HIV-1 chimeric virus (SHIV) (designated as NM-3rN) that contains the HIV-1 env gene and is infectious to macaque monkeys. Challenging the vaccinated macaque monkeys with NM-3rN, we developed an evaluation system for anti-HIV-1 Env-targeted vaccines. For the purpose of making the vaccine, a series of gene-mutated SHIVs were constructed. The monkeys vaccinated with these SHIVs had long-term anti-virus immunities without manifesting the disease, and became resistant to a challenge inoculation with NM-3rN. The sera from a monkey showed that, after the vaccination, the neutralizing antibodies not only against the parental HIV-1 but also against an antigenically different HIV-1 were raised. In vivo experiments confirmed that the vaccinated monkeys were protected from the challenge inoculum of an antigenically different SHIV-MN. Vaccination of monkeys with the attenuated SHIVs showed that further gene-deletion of the SHIV resulted in less immunogenicity. Nevertheless, the attenuated SHIVs had a vaccine effect against the challenge inoculation. In addition to specific immunities including neutralizing antibodies and cytotoxic T cells, a more complicated immune mechanism induced by live vaccine appears to play a role in this protection. Our data suggest that the live vaccine can induce strong and wide-range immunity against HIV-1. These SHIVs should contribute to understanding the pathogenicity of AIDS and to the development of future anti-HIV-1 live vaccines for humans.
缺乏合适的动物模型是开发抗HIV-1疫苗的主要障碍。我们成功构建了一种SIVmac/HIV-1嵌合病毒（SHIV）（命名为NM-3rN），其含有HIV-1 env基因，且对猕猴具有感染性。用NM-3rN攻击接种疫苗的猕猴后，我们建立了一种针对抗HIV-1 Env靶向疫苗的评估系统。为了制备疫苗，构建了一系列基因变异的SHIV。接种这些SHIV的猕猴具有长期抗病毒免疫力且未表现出疾病症状，并对NM-3rN的攻击接种产生抗性。一只猕猴的血清显示，接种疫苗后，不仅产生了针对亲本HIV-1的中和抗体，还产生了针对抗原性不同的HIV-1的中和抗体。体内实验证实，接种疫苗的猕猴受到了抗原性不同的SHIV-MN攻击接种物的保护。用减毒SHIV对猕猴进行接种表明，SHIV进一步的基因缺失导致免疫原性降低。然而，减毒SHIV对攻击接种仍具有疫苗效果。除了包括中和抗体和细胞毒性T细胞在内的特异性免疫外，活疫苗诱导的更复杂的免疫机制似乎在这种保护中发挥了作用。我们的数据表明，活疫苗可诱导针对HIV-1的强大且广泛的免疫。这些SHIV应有助于理解艾滋病的致病性以及未来人类抗HIV-1活疫苗的开发。
