INFECTION OF PIGTAILED MACAQUES W/ SIV/MNE VARIANTS

SIV/MNE 变种的尾猴感染

• 批准号: 6219674
• 负责人: JULIE M. OVERBAUGH
• 金额: $ 12.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6219674
• 关键词: AIDS; Mammalia; animal tissue; communicable diseases; immunology; inflammation; lymphatic system; model design /development; sexually transmitted diseases; virus

Genetic variants of HIV and SIV that evolve during the course of infection and progression to AIDS are phenotypically and antigenically distinct from progenitor viruses present at early stages of infection. These variants are typically T-cell tropic, cytopathic and resistant to neutralizing antibodies. To determine how these variants influence the development of AIDS, macaques were infected with cloned SIVs representing prototype variants from intermediate and late-stage infection having biological characteristics typical of viruses found at similar stages of HIV infection in humans. Like the viruses that typically initiate HIV-1 infections, the parental virus from which these variants evolved is macrophage-tropic, non-cytopathic and non-syncytia-inducing. The levels of virus replication in macaques infected with late variants derived from blood and lymph node were >1000-fold higher than the levels in macaques infected with the non-cytopathic progenitor virus. Both late viruses were cytopathic for CD4+ lymphocytes, but the lymph node virus produced no syncytia, suggesting that a virus's ability to cause cytopathic effects in T cells is more predictive of its pathogenic potential than its phenotype. The intermediate virus, which emerged in the host because it encodes carbohydrates that allowed the virus to escape neutralizing antibodies, was intermediate in its replication and pathogenesis. Thus a neutralization escape mutant that evolves in one host may replicate more efficiently in a new host that can mount a de novo humoral immune response. These data suggest that humoral immune responses play a critical role in driving virus evolution and limiting virus replication. These studies demonstrate that sequential, phenotypic, and antigenic variants represent viruses that have become increasingly fit for replication in the host, and the data support the hypothesis that emerging variants have increased pathogenicity and drive disease progression in SIV an d HIV infection. FUNDING NIH grants RR00166 and AI34251. Kimata, J.T., Mozaffarian, A., and Overbaugh, J. A lymph node-derived cytopathic simian immunodeficiency virus Mne variant replicates in nonstimulated peripheral blood mononuclear cells. J. Virol. 72:245-256, 1998. Kimata, J.T. and Overbaugh, J. The replicative and cytopathic properties of a simian immunodeficiency virus Mne variant are determined by mutations in Gag and Env. J. Med. Primatol. 27:152, 1998 (abstract). Rudensey, L.M., Kimata, J.T., Long, E.M., Chackerian, B., and Overbaugh, J. Changes in the extracellular envelope glycoprotein of variants that evolve during the course of simian immunodeficiency virus SIVmne infection affect neutralizing antibody recognition, syncytium formation, and macrophage tropism but not replication, cytopathicity, or CCR-5 coreceptor recognition. J. Virol. 72:209-217, 1998.

HIV和SIV的遗传变异在感染过程中进化， 感染和发展为AIDS是表型和抗原性 与存在于感染早期阶段的祖病毒不同。 这些变体通常是T细胞嗜性的、致细胞病变的和耐药的 中和抗体 为了确定这些变异如何影响 艾滋病的发展，猕猴感染克隆SIV 代表中晚期的原型变体 具有病毒典型生物特征的感染 在人类感染艾滋病病毒的相似阶段。 就像那些 典型地引发HIV-1感染，亲本病毒， 这些进化的变体是嗜巨噬细胞的，非细胞病变的， 非合胞体诱导。 病毒在猕猴体内的复制水平 感染了来自血液和淋巴结的晚期变异体， 超过1000倍高于猕猴感染的水平 非致细胞病变的祖病毒。 两种晚期病毒都是细胞病变的 对于CD 4+淋巴细胞，但淋巴结病毒不产生合胞体， 这表明病毒在T细胞中引起细胞病变的能力 细胞更能预测其致病潜力， 表型 中间病毒出现在宿主体内， 它编码的碳水化合物能让病毒逃脱中和 抗体，是中间的复制和发病机制。 因此，在一个宿主中进化的中和逃逸突变体可能 在新主机中更高效地复制， 体液免疫反应。 这些数据表明，体液免疫 反应在驱动病毒进化和限制 病毒复制 这些研究表明， 表型和抗原变异体代表的病毒已经成为 越来越适合在主机中复制，并且数据支持 假设新出现的变异增加了致病性， 导致SIV和HIV感染的疾病进展。 资助NIH 赠款RR 00166和AI 34251。 Kimata，J.T.，Mozaffarian，A.，和 Overbaugh，J.淋巴结源性细胞病变性猿猴免疫缺陷 非刺激外周血中病毒Mne变异体复制 单核细胞 J. Virol. 72：245-256，1998. Kimata，J.T.和 Overbaugh，J.《猿猴的复制和细胞病变特性》 免疫缺陷病毒Mne变体由Gag 的Env。J. Med. Primatol. 27：152，1998（摘要）。 鲁登西，LM， Kimata，J.T.，朗，艾米Chackerian，B.，Overbaugh，J. 细胞外被膜糖蛋白的变体在过程中进化 猴免疫缺陷病毒SIVmne感染对病程影响 中和抗体识别、合胞体形成和巨噬细胞 嗜性，但不复制、细胞病变或CCR-5辅助受体 识别. J. Virol. 72：209-217，1998.