CHARACTERIZATION OF MOLECULARLY CLONED SIMIAN HUMAN IMMUNODEFICIENCY VIRUSES

猴免疫缺陷病毒(SIV)感染的研究 亚洲猕猴提供了许多关于糖尿病发病机制的见解。 人类免疫缺陷病毒1型(HIV-1)感染者中的艾滋病。 SIVmac和HIV-1包膜糖蛋白的差异， 然而，限制了SIVmac模型用于研究HIV-1的实用性 致病性的包膜糖蛋白决定因素和检测用 针对HIV-1包膜糖蛋白的疫苗策略。 猴-人嵌合免疫缺陷病毒的体内传代 (SHIV-89.6)表达HIV-1 Tat、rev、VPU和env基因 致病病毒(SIV-89.6P)诱导快速的CD4+淋巴细胞耗竭 和恒河猴的艾滋病样疾病(J Virol 70：6922-6928,1996)。 由SHV-89.6P的一些前病毒克隆产生的病毒引起了 并在很高比例的CD_4~+淋巴细胞显著下降 给猕猴接种疫苗。核苷酸变化可能是导致 SH IV-89.6P的毒力增强仅限于env、Tat或 长末端重复序列，大多数观察到的变化是在 环境Env的核苷酸变化改变了gp120中的12个氨基酸。 和gp41外部结构域，以及env中140个碱基的缺失导致 SIVmac gp41羧基末端的取代 HIV-1 gp41糖蛋白的糖蛋白。这两个级别 病毒血症与HIV-1包膜糖蛋白的结构 胞外区单独对CD4+的效率有贡献 T淋巴细胞耗尽。猪瘟病毒包膜糖蛋白的研究 高效导致CD_4~+T淋巴细胞丧失的重组SHIV 显示趋化因子受体结合和膜融合增加 与致病性较低的病毒相比，病毒的致病能力更强。这些 研究确定HIV-1包膜糖蛋白胞外区为 体内CD4+T淋巴细胞丢失的决定因素并提供一种 研究致病机制的基础。为协作提供资金 与莱特文博士合作，哈佛大学出版了卡尔松GB，哈洛兰 首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容 埃特马德-莫哈达姆B，Desjardins E，Wyatt R，Gerard NP，Marcon L， 首页--期刊主要分类--期刊细介绍--期刊题录与期刊详细文摘内容 糖蛋白胞外区决定CD_4~+T淋巴细胞的效率 猴-人类免疫缺陷病毒感染的猕猴的耗竭。J EXP Med 188(6)：1159-1171,1998。

The study of simian immunodeficiency virus (SIV) infection in Asian macaques has provided numerous insights into the pathogenesis of AIDS in human immunodeficiency virus type 1 (HIV-1)-infected humans. The divergence of the envelope glycoproteins of SIVmac and HIV-1, however, limit the utility of the SIVmac model for studying HIV-1 envelope glycoprotein determinants of pathogenicity, and for testing vaccine strategies directed against the HIV-1 envelope glycoproteins. In vivo passage of a chimeric simian-human immunodeficiency virus (SHIV-89.6) expressing HIV-1 tat, rev, vpu and env genes generated pathogenic virus (SHIV-89.6P) inducing rapid CD4+ lymphocyte depletion and AIDS-like illness in rhesus monkeys (J Virol 70:6922-6928, 1996). Virus generated from some proviral clones of SHIV-89.6P caused a rapid and profound decline of CD4+ lymphocytes in a high percentage of inoculated macaques. Nucleotide changes potentially responsible for increased virulence of SH IV-89.6P were limited to the env, tat or long terminal repeat sequences, with most of the observed changes in env. Nucleotide changes in env altered 12 amino acids in the gp120 and gp41 exterior domains, and a 140 bp deletion in env resulted in the substitution of the carboxyl terminus of the SIVmac gp41 glycoprotein for that of the HIV-1 gp41 glycoprotein. Both the level of viremia and the structure of the HIV-1 envelope glycoprotein ectodomains individually contributed to the efficiency with which CD4+ T lymphocytes were depleted. The envelope glycoproteins of recombinant SHIVs that efficiently caused loss of CD4+ T lymphocytes exhibited increased chemokine receptor binding and membrane-fusing capacity compared with those of less pathogenic viruses. These studies identify the HIV-1 envelope glycoprotein ectodomains as determinants of CD4+ T lymphocyte loss in vivo and provide a foundation for studying pathogenic mechanisms. FUNDING Collaboration with Dr. Letvin, Harvard University PUBLICATIONS Karlsson GB, Halloran M, Schenten D, Lee J, Racz P, Tenner-Racz K, Manola J, Gelman R, Etemad-Moghadam B, Desjardins E, Wyatt R, Gerard NP, Marcon L, Margolin D, Fanton J, Axthelm MK, Letvin NL, Sodroski J. The envelope glycoprotein ectodomains determine the efficiency of CD4+ T lymphocyte depletion in simian-human immunodeficiency virus-infected macaques. J Exp Med 188(6):1159-1171, 1998.