Mothé Bianca R, Horton Helen, Carter Donald K, Allen Todd M, Liebl Max E, Skinner Pam, Vogel Thorsten U, Fuenger Sarah, Vielhuber Kathy, Rehrauer William, Wilson Nancy, Franchini Genoveffa, Altman John D, Haase Ashley, Picker Louis J, Allison David B, Watkins David I
Wisconsin Regional Primate Research Center, University of Wisconsin, Madison, Wisconsin 53715, USA.
J Virol. 2002 Jan;76(2):875-84. doi: 10.1128/jvi.76.2.875-884.2002.
Cytotoxic T-lymphocyte (CTL) responses are thought to control human immunodeficiency virus replication during the acute phase of infection. Understanding the CD8(+) T-cell immune responses early after infection may, therefore, be important to vaccine design. Analyzing these responses in humans is difficult since few patients are diagnosed during early infection. Additionally, patients are infected by a variety of viral subtypes, making it hard to design reagents to measure their acute-phase immune responses. Given the complexities in evaluating acute-phase CD8(+) responses in humans, we analyzed these important immune responses in rhesus macaques expressing a common rhesus macaque major histocompatibility complex class I molecule (Mamu-A01) for which we had developed a variety of immunological assays. We infected eight Mamu-A01-positive macaques and five Mamu-A01-negative macaques with the molecularly cloned virus SIV(mac)239 and determined all of the simian immunodeficiency virus-specific CD8(+) T-cell responses against overlapping peptides spanning the entire virus. We also monitored the evolution of particular CD8(+) T-cell responses by tetramer staining of peripheral lymphocytes as well as lymph node cells in situ. In this first analysis of the entire CD8(+) immune response to autologous virus we show that between 2 and 12 responses are detected during the acute phase in each animal. CTL against the early proteins (Tat, Rev, and Nef) and against regulatory proteins Vif and Vpr dominated the acute phase. Interestingly, CD8(+) responses against Mamu-A01-restricted epitopes Tat(28-35)SL8 and Gag(181-189)CM9 were immunodominant in the acute phase. After the acute phase, however, this pattern of reactivity changed, and the Mamu-A01-restricted response against the Gag(181-189)CM9 epitope became dominant. In most of the Mamu-A01-positive macaques tested, CTL responses against epitopes bound by Mamu-A*01 dominated the CD8(+) cellular immune response.
细胞毒性T淋巴细胞（CTL）反应被认为在感染急性期可控制人类免疫缺陷病毒的复制。因此，了解感染后早期的CD8(+) T细胞免疫反应可能对疫苗设计很重要。由于在早期感染期间很少有患者被诊断出来，所以在人类中分析这些反应很困难。此外，患者感染的是多种病毒亚型，这使得设计试剂来测量他们的急性期免疫反应变得困难。鉴于评估人类急性期CD8(+)反应的复杂性，我们在表达常见恒河猴主要组织相容性复合体I类分子（Mamu-A01）的恒河猴中分析了这些重要的免疫反应，我们已经针对该分子开发了多种免疫测定方法。我们用分子克隆病毒SIV(mac)239感染了8只Mamu-A01阳性猕猴和5只Mamu-A01阴性猕猴，并确定了所有针对覆盖整个病毒的重叠肽段的猿猴免疫缺陷病毒特异性CD8(+) T细胞反应。我们还通过外周淋巴细胞以及原位淋巴结细胞的四聚体染色监测了特定CD8(+) T细胞反应的演变。在对自体病毒的整个CD8(+)免疫反应的首次分析中，我们表明在急性期每只动物中检测到2至12种反应。针对早期蛋白（Tat、Rev和Nef）以及调节蛋白Vif和Vpr的CTL在急性期占主导地位。有趣的是，针对Mamu-A01限制性表位Tat(28-35)SL8和Gag(181-189)CM9的CD8(+)反应在急性期具有免疫优势。然而，急性期过后，这种反应模式发生了变化，针对Gag(181-189)CM9表位的Mamu-A01限制性反应变得占主导地位。在大多数测试的Mamu-A01阳性猕猴中，针对与Mamu-A*01结合的表位的CTL反应在CD8(+)细胞免疫反应中占主导地位。
