Mechanisms of Feline Lentivirus Control and Interference

描述(申请人提供)：尽管本土非洲猴慢病毒传播给人类或亚洲猕猴导致了新宿主的致病后果，但越来越明显的是，致病性跨物种慢病毒感染是一种例外情况。最近的研究表明，先天的细胞限制因素是限制这种感染的关键，慢病毒对新宿主的适应需要辅助基因结构的改变，即病毒感染性因子(Vif)。为了研究这个问题，我们建立了一个跨物种慢病毒传播的猫科动物模型，这种模型会导致生产性的、但退行性的无毒感染，并确定这种感染可以减弱随后的强毒猫免疫缺陷病毒(FIV)的攻击。在最初的赠款周期中公布的数据表明，先天细胞反应，即细胞因子表达谱和导致高病毒错误负担的胞苷脱氨酶(CD)活性，对于宿主病毒控制比获得性免疫反应更重要--获得性免疫反应是在病毒下调之前而不是之后。此外，在感染强毒PUMA慢病毒(PLV-1695)的猫中，毒力FIV-C-PG疾病的减弱(即防止CD4+T细胞耗尽和调节病毒设定点)与独特的FIV分子进化有关，与单独感染强毒FIV-C-PG的猫相比，维持促炎症细胞因子谱-尽管FIV和PLV之间在受体使用和靶细胞分布方面存在差异，疾病仍发生调节。在这里，我们建议推进这一独特的猫科动物模型，以解决慢病毒生物学中的重要问题：(A)宿主的先天活动(由CD样超突变和细胞因子细胞信号定义)如何与疾病的减弱有关？以及(B)Vif在调节强毒慢病毒挑战中扮演什么角色？为了回答这些问题，我们建议：(1)确定先前感染PLV-1695是否增加了FIV-C-PG攻击后的过度突变、错误负担和组织特异性胞苷脱氨酶活性/细胞因子的表达；以及(2)确定Vif是否调节CD活性和细胞因子激活作为一种减弱机制。这些实验为评估对艾滋病毒/艾滋病的保护性免疫提出了一个新的范式--即通过暴露于无毒的、非适应的慢病毒来增强早期的先天免疫参数，可以提供对强毒力、宿主适应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.