Etemad-Moghadam Bijan, Rhone Daniela, Steenbeke Tavis, Sun Ying, Manola Judith, Gelman Rebecca, Fanton John W, Racz Paul, Tenner-Racz Klara, Axthelm Michael K, Letvin Norman L, Sodroski Joseph
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Vaccine. 2002 May 6;20(15):1934-7. doi: 10.1016/s0264-410x(02)00072-5.
The efficacy of candidate AIDS vaccines to mediate protection against viral infection and pathogenesis is evaluated, at a preclinical stage, in animal models. One model that is favored because the infecting virus is closely related to HIV-1 and because of the rapidity of pathogenic outcomes is the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae. We investigated the basis for the depletion of CD4(+) T lymphocytes in a SHIV-macaque model. Molecularly cloned SHIVs, SHIV-89.6 and SHIV-KB9, differ in the ability to cause CD4(+) T-cell loss at a given level of virus replication in monkeys. The envelope glycoproteins of the pathogenic SHIV-KB9 mediate membrane-fusion in cultured T lymphocytes more efficiently than the envelope glycoproteins of the non-pathogenic SHIV-89.6. The minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity was sufficient to convert SHIV-89.6 into a virus that causes profound CD4(+) T-cell depletion in monkeys. Conversely, two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins also attenuated the CD4(+) T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4(+) T lymphocytes in vivo.
在临床前阶段，通过动物模型评估候选艾滋病疫苗介导预防病毒感染和发病的功效。一种受到青睐的模型是用猿猴 - 人类免疫缺陷病毒（SHIV）嵌合体感染旧世界猴，因为感染病毒与HIV - 1密切相关，且发病结果迅速。我们在SHIV - 猕猴模型中研究了CD4(+) T淋巴细胞耗竭的基础。分子克隆的SHIV，即SHIV - 89.6和SHIV - KB9，在猴子体内给定病毒复制水平下导致CD4(+) T细胞损失的能力有所不同。致病性SHIV - KB9的包膜糖蛋白在培养的T淋巴细胞中介导膜融合的效率高于非致病性SHIV - 89.6的包膜糖蛋白。指定这种膜融合能力增加的最小包膜糖蛋白区域足以将SHIV - 89.6转化为一种能在猴子体内导致严重CD4(+) T细胞耗竭的病毒。相反，两个单氨基酸变化降低了SHIV - KB9包膜糖蛋白的膜融合能力，也减弱了在SHIV感染的猴子中给定病毒复制水平下伴随的CD4(+) T细胞破坏。因此，HIV - 1包膜糖蛋白融合膜的能力（这在体外病毒细胞病变效应的诱导中已被涉及）有助于致病性SHIV在体内耗竭CD4(+) T淋巴细胞的能力。
