Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: Inverse relationship of degree of protection with level of attenuation
Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: Inverse relationship of degree of protection with level of attenuation
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DOI：
10.1128/jvi.73.6.4952-4961.1999
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发表时间：
1999-06-01
影响因子：
5.4
通讯作者：
Desrosiers, RC
中科院分区：
文献类型：
--
作者：
Johnson, RP;Lifson, JD;Desrosiers, RC
三种不同的缺失突变体的猴免疫缺陷病毒（SIV），在他们的减毒水平不同的能力，以保护免受粘膜攻击的致病性SIV进行了测试。四只雌性恒河猴通过静脉内接种SIVmac 239 Delta 3，四只SIVmac 239 Delta 3X和四只SIVmac 239 Delta 4进行疫苗接种。这三种疫苗株表现出渐增的减毒水平：Delta 3 < Delta 3X < Delta 4。在接种后61周，通过阴道暴露于未克隆的致病性SIVmac 251来攻击接种疫苗的猴。根据血浆中的病毒RNA载量、外周血中的细胞相关病毒载量和CD 4细胞计数，在所有三组接种猴中均观察到强保护作用。然而，保护程度与减毒水平呈负相关;减毒程度最低的毒株SIVmac 239 Delta 3提供了最大的保护。Delta 3X组中的一只猴子和Delta 4组中的两只猴子显然被攻击病毒双重感染，但这些动物血浆中的SIV RNA水平明显低于平行攻击的未感染动物。对阴道攻击的保护似乎比对静脉内攻击的保护更容易实现，因为其他四只SIVmac 239 Delta 4疫苗接种的猴子没有显示出保护，当用低得多的接种物的相同的攻击病毒储备液进行静脉内攻击时，免疫组在没有可检测到的血清中和活性的情况下发生，似乎与早期SIV特异性细胞毒性T细胞的发展有关。淋巴细胞反应我们的结果表明，粘膜保护可以通过在攻击时间之前用高度减毒的SIVmac 239 Delta 4全身免疫超过1年来实现。
Three different deletion mutants of simian immunodeficiency virus (SIV) that vary in their levels of attenuation were tested for the ability to protect against mucosal challenge with pathogenic SIV. Four female rhesus monkeys were vaccinated by intravenous inoculation with SIVmac239 Delta 3, four with SIVmac239 Delta 3X, and four with SIVmac239 Delta 4. These three vaccine strains exhibit increasing levels of attenuation: Delta 3 < Delta 3X < Delta 4. The vaccinated monkeys were challenged by vaginal exposure to uncloned, pathogenic SIVmac251 at 61 weeks after the time of vaccination. On the basis of viral RNA loads in plasma, cell-associated virus loads in peripheral blood, and CD4 cell counts, strong protective effects were observed in all three groups of vaccinated monkeys. However, the degree of protection correlated inversely with the level of attenuation; the least-attenuated strain, SIVmac239 Delta 3, gave the greatest protection. One monkey in the Delta 3X group and two in the Delta 4 group clearly became superinfected by the challenge virus, but these animals had levels of SIV RNA in plasma that were considerably lower than those of naive animals that were challenged in parallel. Protection against vaginal challenge appears easier to achieve than protection against intravenous challenge, since four other SIVmac239 Delta 4-vaccinated monkeys showed no protection, when challenged intravenously with a much lower inoculum of the same challenge virus stock Protection against vaginal challenge in the Delta 4-vaccinated group occurred in the absence of detectable serum neutralizing activities and appeared to be associated with the development of an early SIV-specific cytotoxic-T-lymphocyte response. Our results demonstrate that mucosal protection can be achieved by systemic immunization with the highly attenuated SIVmac239 Delta 4 more than 1 year prior to the time of challenge.