Mechanisms of Feline Lentivirus Control and Interference

描述（由申请人提供）：尽管非洲本土猴慢病毒传播给人类或亚洲猕猴对新宿主造成了致病性后果，但越来越清楚的是，致病性跨物种慢病毒感染是一种罕见的情况。最近的研究表明，先天细胞限制因子是限制这种感染的关键，慢病毒适应新宿主需要改变辅助基因结构，即病毒感染因子（Vif）。为了研究这个问题，我们开发了一种跨物种慢病毒传播的猫模型，该模型导致生产性的，但退行性的，无毒的感染，并确定这种感染减弱了随后的毒性猫免疫缺陷病毒（FIV）攻击。在最初的资助周期中发表的数据表明，先天细胞反应，即细胞因子表达谱和胞苷脱氨酶样（CD）活性导致高病毒错误负担，对宿主病毒控制比适应性免疫反应更重要，适应性免疫反应紧随病毒下调而不是先于病毒下调。此外，在感染无毒性美洲狮慢病毒（PLV-1695）的猫中，强毒FIV- c - pg疾病衰减（即免受CD4+ T细胞耗损和病毒设定点的调节）与独特的FIV分子进化以及与单独感染强毒FIV- c - pg的猫相比，促炎细胞因子谱的维持有关，尽管FIV和PLV之间的受体使用和靶细胞分布存在差异，但疾病调节仍会发生。在这里，我们建议推进这种独特的猫模型来解决慢病毒生物学中的重要问题：(a)宿主先天活性（由cd样超突变和细胞因子细胞信号传导定义）如何与疾病的衰减相关？(b) Vif在调节毒性慢病毒攻击中起什么作用？为了回答这些问题，我们提出：(1)确定先前的PLV-1695感染是否会增加FIV-C-PG攻击后的高突变、错误负担和组织特异性胞苷脱氨基酶活性/细胞因子表达；(2)确定Vif是否作为一种衰减机制调节CD活性和细胞因子活化。这些实验为评估对HIV/ aids的保护性免疫提供了一个新的范式，即通过暴露于一种无毒的、非适应性的慢病毒来增强早期先天免疫参数，可以提供对一种有毒的、宿主适应性的慢病毒的交叉保护活性，因此，这些研究具有重要的公共卫生意义。

DESCRIPTION (provided by applicant): Though transmission of indigenous African monkey lentiviruses to humans or to Asian macaques has resulted pathogenic consequences for the new host, it is becoming increasingly clear that pathogenic cross- species lentiviral infection is an exceptional occurrence. Recent studies indicate innate cellular restriction factors are key to limiting such infections, and that lentiviral adaptation to a new host requires alterations in accessory gene structure, i.e., viral infectivity factor (Vif). To study this issue, we developed a feline model of cross-species lentiviral transmission that results in productive, yet regressive, avirulent infection, and have determined that such infection attenuates subsequent virulent feline immunodeficiency virus (FIV) challenge. Data published during the initial grant cycle demonstrate that innate cellular responses, namely cytokine expression profiles and cytidine deaminase-like (CD) activity resulting in high viral error burden, are more significant for host viral control than adaptive immune responses-which follow rather than precede viral down regulation. Moreover, virulent FIV-C-PG disease attenuation (i.e. protection from CD4+ T cell depletion and modulation of viral set point) in cats infected with avirulent puma lentivirus (PLV-1695), is associated with unique FIV molecular evolution, and maintenance of a proinflammatory cytokine profile vs. cats infected with virulent FIV-C-PG alone-and disease modulation occurs despite disparities in receptor use and target cell distribution between FIV and PLV. Here we propose to advance this unique feline model to address important questions in lentivirus biology: (a) How does host innate activity (defined by CD-like hypermutation and cytokine cell-signaling) relate to attenuation of disease? and (b) What role does Vif play in modulating virulent lentiviral challenge? To answer these questions, we propose: (1) To determine whether previous PLV-1695 infection enhances hypermutation, error burden, and tissue-specific cytidine deaminase activity/cytokine expression after FIV-C-PG challenge; and, (2) To determine whether Vif modulates CD activity and cytokine activation as a mechanism of attenuation. These experiments pose a new paradigm for assessment of protective immunity against HIV/AIDS-namely, that enhancement of early innate immune parameters by exposure to an avirulent, non-adapted lentivirus can provide cross-protective activity against a virulent, host-adapted lentivirus, and as such, these studies are of great public health significance.