CHARACTERIZATION OF MOLECULARLY CLONED SIMIAN HUMAN IMMUNODEFICIENCY VIRUSES

猴免疫缺陷病毒（SIV）感染的研究 亚洲猕猴已经提供了许多见解的发病机制， 人类免疫缺陷病毒1型（HIV-1）感染者的艾滋病。 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簇，以及用于检测 针对HIV-1包膜糖蛋白的疫苗策略。 嵌合猴-人免疫缺陷病毒的体内传代 产生表达HIV-1达特、rev、vpu和env基因的SHIV-89.6 致病性病毒（SHIV-89.6P）诱导快速CD 4+淋巴细胞耗竭 和恒河猴中的AIDS样疾病（J Virol 70：6922-6928，1996）。 从SHIV-89.6P的一些前病毒克隆产生的病毒引起了快速的免疫反应。 和CD 4+淋巴细胞的大幅下降， 接种的猕猴。 核苷酸变化可能导致 SH IV-89.6P的毒力增加仅限于env、达特或 长末端重复序列，与大多数观察到的变化， env. env中核苷酸的改变改变了gp 120中的12个氨基酸 和gp 41外部结构域，以及env中140 bp的缺失导致 SIVmac gp 41羧基端的取代 HIV-1 gp 41糖蛋白。 无论是水平 HIV-1包膜糖蛋白的结构 胞外结构域单独地有助于CD 4 + T淋巴细胞耗竭。 的包膜糖蛋白 重组SHIV可有效引起CD 4 + T淋巴细胞的丢失 表现出趋化因子受体结合和膜融合增加 与那些致病性较低的病毒相比。 这些 研究确定HIV-1包膜糖蛋白胞外域为 决定因素的CD 4 + T淋巴细胞损失在体内，并提供了一个 研究致病机制的基础。 资助合作 与Letvin博士，哈佛大学出版物Karlsson GB，Halloran M，Schenten D，Lee J，Racz P，Tenner-Racz K，马诺拉J，Gelman R， Etemad-Moghadam B，Desjardins E，Wyatt R，Gerard NP，Marcon L， Margolin D，Fanton J，Axthelm MK，Letvin NL，Sodroski J.信封 糖蛋白胞外域决定CD 4 + T淋巴细胞的效率 在猿猴-人类免疫缺陷病毒感染的猕猴中的消耗。 J 实验医学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.