INFECTION OF PIGTAILED MACAQUES W/ SIV/MNE VARIANTS

SIV/MNE 变种的尾猴感染

• 批准号: 6116359
• 负责人: JULIE M. OVERBAUGH
• 金额: $ 8.67万
• 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/6116359
• 关键词: AIDS; Mammalia; Primates; animal tissue; immunology; infection; inflammation; lymphatic system; model design /development; sexually transmitted diseases; virus

Simian immunodeficieny virus isolated from Macaca nemestrina (SIVmne), like HIV, evolves from a slowly replicating, minimally cytopathic, nonsyncytium-inducing (slow-low/NSI) virus to a population of rapidly replicating, highly cytopathic, syncytium-inducing (rapid-high/SI) viruses during the course of an infection. Because the changes in viral phenotype are associated with high viral loads, CD4+ T-cell decline, and progression to AIDS, they are believed to be indicative of increased virulence. The primary goal of this study is to determine whether the rapid-high/SI viruses are more pathogenic than slow-low/NSI viruses, and to identify the determinants responsible for the change in phenotype. Our previous studies suggested that the phenotypic switch in SIVmne was not the result of mutations in the envelope surface glycoprotein (Env SU). Therefore, to define the viral determinants responsible for the change in phenotype, we molecularly cloned a rapid-high/SI variant (designated SIVmne170) from the peripheral blood mononuclear cells (PBMCs) of a pigtailed macaque that was inoculated with a slow-low/NSI molecular clone, SIVMneCL8. Compared with the parent SIVMneCL8, SIVMne170 was syncytium-inducing, rapidly replicating, and highly cytopathic. The genetic determinants that conferred SIVMne170's phenotype mapped to the viral core proteins, Gag capsid and nucleocapsid, and the Env SU and transmembrane (TM) domains. We also cloned a second variant virus (designated SIVMne027) from lymph node tissue of a macaque. Interestingly, while SIVMne027 was also rapidly replicating and highly cytopathic compared with SIVMneCL8, it was nonsyncytium-inducing. Furthermore, SIVMne027 also had the capacity to replicate in nonstimulated macaque PBMCs. To test the pathogenicity of SIVMne170 and SIVMne027 in vivo, we infected juvenile pigtailed macaques by intravenous inoculation. Our preliminary data demonstrate that both variants may be more pathogenic than the slow-low/NSI parent virus, and that the SI property may not necessarily influence pathogenesis. Instead, the in vitro replicative and cytopathic properties may be more predictive of virulence in vivo. Together, these studies may provide insight into the significance that mutations in Gag and Env TM play in influencing SIV pathogenesis.

猴免疫缺陷病毒（SIVmne），从猕猴nemestrina分离，像艾滋病毒，从一个缓慢复制，最小的细胞病变，非合胞体诱导（慢-低/NSI）病毒的人口迅速复制，高度细胞病变，合胞体诱导（快-高/SI）病毒在感染过程中。 由于病毒表型的变化与高病毒载量、CD 4 + T细胞下降和进展为AIDS相关，因此认为它们指示毒力增加。 本研究的主要目的是确定快速高/SI病毒是否比慢速低/NSI病毒更具致病性，并确定表型变化的决定因素。 我们以前的研究表明，SIVmne的表型转换不是包膜表面糖蛋白（Env SU）突变的结果。 因此，为了确定负责表型变化的病毒决定因素，我们从接种慢-低/NSI分子克隆SIVMneCL 8的猪尾猕猴的外周血单核细胞（PBMC）中分子克隆了一种快速-高/SI变体（命名为SIVmne 170）。 与亲本SIVMneCL 8相比，SIVMne 170具有合胞体诱导、快速复制和高度细胞病变的特性。赋予SIVMne 170的表型的遗传决定因素映射到病毒核心蛋白、Gag衣壳和核衣壳以及Env SU和跨膜（TM）结构域。 我们还从猕猴的淋巴结组织中克隆了第二种变异病毒（命名为SIVMne 027）。 有趣的是，虽然SIVMne 027与SIVMneCL 8相比也是快速复制和高度致细胞病变的，但它是非合胞体诱导的。 此外，SIVMne 027还具有在未刺激的猕猴PBMC中复制的能力。 为了测试SIVMne 170和SIVMne 027在体内的致病性，我们通过静脉接种感染幼年短尾猴。 我们的初步数据表明，这两种变体可能比慢-低/NSI亲本病毒更具致病性，SI特性可能不一定影响发病机制。 相反，体外复制和细胞病变特性可能更能预测体内毒力。 总之，这些研究可以提供洞察的意义，在Gag和Env TM突变影响SIV发病机制。