Central nervous system-specific consequences of simian immunodeficiency virus Gag escape from major histocompatibility complex class I-mediated control.
Central nervous system-specific consequences of simian immunodeficiency virus Gag escape from major histocompatibility complex class I-mediated control.
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DOI：
10.1007/s13365-015-0420-5
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发表时间：
2016-08
影响因子：
3.2
通讯作者：
Mankowski JL
中科院分区：
文献类型：
--
作者：
Beck SE;Queen SE;Viscidi R;Johnson D;Kent SJ;Adams RJ;Tarwater PM;Mankowski JL
在HIV流行的第四个十年中，宿主免疫与HIV中枢神经系统(CNS)疾病之间的关系仍未完全清楚。使用猴免疫缺陷病毒(SIV)/猕猴模型，我们检测了表达MHC I类等位基因Mane-A1*084：01的辫尾猕猴的中枢神经系统结果，该等位基因对SIV诱导的CNS疾病具有抵抗力，并诱导原型病毒逃逸突变Gag K165R。与SIV/17E-Fr相比，将Gag K165R插入神经毒力克隆SIV/17E-Fr可降低病毒的体外复制。我们还发现，接种SIV/17E-Fr K165R的猕猴的脑脊液病毒载量低于野生型，但血浆中的病毒载量低于野生型。虽然逃逸突变K165R在血浆中基因稳定，但在脑脊液和小胶质细胞培养中迅速恢复为野生型Gag KP9。我们用Gag KP9病毒样颗粒(VLP)疫苗免疫Mane-A*084：01阳性的尾辫猕猴，诱导了强大的Gag KP9特异性CTL四聚体反应。在SIV/17E-Fr攻击后，接种疫苗的动物脑脊液中的SIV RNA低于未接种的对照组，但在血浆病毒载量方面没有差异。这些数据清楚地表明，随着新的治疗性疫苗接种策略的出现，CNS中的病毒适合性与外围地区截然不同，并强调了了解CNS疾病中病毒逃逸的后果的必要性。
In the fourth decade of the HIV epidemic, the relationship between host immunity and HIV central nervous system (CNS) disease remains incompletely understood. Using a simian immunodeficiency virus (SIV)/macaque model, we examined CNS outcomes in pigtailed macaques expressing the MHC class I allele Mane-A1*084:01 which confers resistance to SIV-induced CNS disease and induces the prototypic viral escape mutation Gag K165R. Insertion of gag K165R into the neurovirulent clone SIV/17E-Fr reduced viral replication in vitro compared to SIV/17E-Fr. We also found lower CSF, but not plasma, viral loads in macaques inoculated with SIV/17E-Fr K165R versus those inoculated with wildtype. Although escape mutation K165R was genotypically stable in plasma, it rapidly reverted to wildtype Gag KP9 in both CSF and in microglia cultures. We induced robust Gag KP9-specific CTL tetramer responses by vaccinating Mane-A*084:01-positive pigtailed macaques with a Gag KP9 virus-like particle (VLP) vaccine. Upon SIV/17E-Fr challenge, vaccinated animals had lower SIV RNA in CSF compared to unvaccinated controls, but showed no difference in plasma viral loads. These data clearly demonstrate that viral fitness in the CNS is distinct from the periphery and underscores the necessity of understanding the consequences of viral escape in CNS disease with the advent of new therapeutic vaccination strategies.