Cytotoxic T lymphocyte-based control of simian immunodeficiency virus replication in a preclinical AIDS vaccine trial
Cytotoxic T lymphocyte-based control of simian immunodeficiency virus replication in a preclinical AIDS vaccine trial
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DOI：
10.1084/jem.20040432
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发表时间：
2004-06-21
影响因子：
15.3
通讯作者：
Nagai, Y
中科院分区：
文献类型：
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作者：
Matano, T;Kobayashi, M;Nagai, Y
最近，令人鼓舞的艾滋病疫苗在猕猴中的试验表明，细胞毒性T淋巴细胞（CTL）在控制猿类人类免疫缺陷病毒SHIV89.6P诱导急性CD 4（+）T细胞耗竭。然而，这些疫苗方案都未能成功遏制诱发慢性疾病进展的致病性猿猴免疫缺陷病毒（SIV）的复制。事实上，疫苗诱导的CTL是否能控制SIV的复制仍不清楚。在这里，我们显示的证据表明，疫苗诱导的CTL控制SIVmac 239复制恒河猴。用SIVmac 239静脉内攻击用DNA-初免/表达GAG的仙台病毒载体加强免疫的八只猕猴。5名接种者控制病毒复制，感染5周后检测不到血浆病毒血症。来自所有这五只猕猴的CTL快速选择Gag中的逃逸突变，表明疫苗诱导的CTL成功地包含了攻击病毒的复制。有趣的是，对三种疫苗中选择的逃逸变异体的分析显示，与SIVmac 239相比，逃逸变异体病毒处于复制劣势。这些发现表明疫苗诱导的CTL已经“削弱”了攻击病毒。我们的研究结果表明，疫苗诱导的高效CTL可以导致高致病性免疫缺陷病毒的复制遏制。
Recently, encouraging AIDS vaccine trials in macaques have implicated cytotoxic T lymphocytes (CTLs) in the control of the simian human immunodeficiency virus SHIV89.6P that induces acute CD4(+) T cell depletion. However, none of these vaccine regimens have been successful in the containment of replication of the pathogenic simian immunodeficiency viruses (SIVs) that induce chronic disease progression. Indeed, it has remained unclear if vaccine-induced CTL can control SIV replication. Here, we show evidence suggesting that vaccine-induced CTLs control SIVmac239 replication in rhesus macaques. Eight macaques vaccinated with DNA-prime/Gag-expressing Sendai virus vector boost were challenged intravenously with SIVmac239. Five of the vaccinees controlled viral replication and had undetectable plasma viremia after 5 wk of infection. CTLs from all of these five macaques rapidly selected for escape mutations in Gag, indicating that vaccine-induced CTLs successfully contained replication of the challenge virus. Interestingly, analysis of the escape variant selected in three vaccinees that share a major histocompatibility complex class I haplotype revealed that the escape variant virus was at a replicative disadvantage compared with SIVmac239. These findings suggested that the vaccine-induced CTLs had "crippled" the challenge virus. Our results indicate that vaccine induction of highly effective CTLs can result in the containment of replication of a highly pathogenic immunodeficiency virus.