Receptor usage and pathogenicity of feline lentiviruses

描述（由申请人提供）：本项目的总体目标是研究病毒-受体相互作用在艾滋病发病机制中的作用。该项目将建立在我们早期的工作表明，CXCR-4和CD 134是主要的辅助受体和主要的结合受体分别为猫免疫缺陷病毒（FIV），慢病毒的家猫。在猫，FIV感染诱导免疫缺陷综合征类似艾滋病在HIV感染的人。在拟议的研究中，我们将询问受体使用是否是FIV致病性的主要决定因素，以及在早期和晚期感染期间是否存在具有不同受体使用的病毒。 在之前的资助期间，我们发现FIV的原代毒株需要CD 134和CXCR-4的共表达才能感染靶细胞。这种竞争性更新的目的1将询问在不同的FIV分离株中CD 134的使用是否普遍存在，检查来自不同地理来源和遗传背景的病毒的受体使用。 目的2将集中在病毒包膜糖蛋白（Env）和CD 134之间的相互作用，映射病毒结合位点，并询问Env结合是否干扰CD 134在抗原特异性T细胞的扩增和存活中的正常细胞功能。本节将讨论Env-CD 134相互作用如何促进猫中AIDS的发病机制，这对解释使用FIV作为AIDS动物模型的研究具有重要意义。 最后，在目标3中，我们将研究在早期和晚期感染中是否存在具有不同生物表型的病毒。初步观察表明，来自无症状猫的病毒与来自有症状猫的病毒相比，在体内具有不同的细胞嗜性、受体用途和生物学特性。此外，由于它们在体内获得更高的病毒载量，并且在早期感染中占主导地位，因此这些分离株很可能是在田间传播的分离株。由于迄今为止研究的大多数分离株都来自表现出感染临床症状的动物，因此这些研究对于选择病毒以供未来在这种广泛使用的艾滋病小动物模型中进行新型疫苗和治疗方法的试验具有极其重要的意义。

DESCRIPTION (provided by applicant): The overall aim of this project is to examine the role of the virus-receptor interaction in the pathogenesis of AIDS. The project will build upon our earlier work demonstrating that CXCR-4 and CD134 are the major co-receptor and primary binding receptor respectively for feline immunodeficiency virus (FIV), the lentivirus of the domestic cat. In the cat, FIV infection induces an immunodeficiency syndrome similar to AIDS in HIV-infected humans. In the proposed studies, we will ask whether receptor usage is a major determinant of FIV pathogenicity and whether viruses with distinct receptor usages are present during early and late infection. In the previous funding period, we showed that primary strains of FIV require the co-expression of CD134 in addition to CXCR-4 in order to infect target cells. Aim 1 of this competing renewal will ask whether CD134-usage is ubiquitous amongst diverse isolates of FIV, examining the receptor usage of viruses from distinct geographical origins and genetic backgrounds. Aim 2 will focus on the interaction between the viral envelope glycoprotein (Env) and CD134, mapping the viral binding site and asking whether Env binding perturbs the normal cellular function of CD134 in the expansion and survival of antigen-specific T cells. This section will address how the Env-CD134 interaction contributes to the pathogenesis of AIDS in the cat, of great significance to the interpretation of studies using FIV as an animal model for AIDS. Finally, in Aim 3 we will investigate whether viruses with distinct biological phenotypes exist in early and late infection. Preliminary observations suggest that viruses derived from asymptomatic cats have distinct cell tropisms, receptor usages and biological properties in vivo compared to those derived from symptomatic cats. Moreover, as they achieve higher viral loads in vivo, and predominate in early infection, it is likely that these isolates are the ones that are transmitted in the field. As the majority of isolates studied to date have been derived from animals displaying clinical signs of infection, these studies are of profound importance to the selection of viruses for future trials of novel vaccines and therapeutics in this widely used small animal model of AIDS.