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工作的基础上，证明CXCR-4和CD134分别是猫免疫缺陷病毒(FIV)的主要辅助受体和主要结合受体。在猫身上，FIV感染会导致一种免疫缺陷综合症，类似于艾滋病毒感染者的艾滋病。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，以及在感染早期和晚期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的主要毒株除了CXCR-4外，还需要CD134的共同表达才能感染靶细胞。这一竞争性更新的目标1将询问CD134-使用是否在不同的FIV分离株中普遍存在，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研究病毒包膜糖蛋白(Env)与CD134的相互作用，定位病毒结合部位，探讨在抗原特异性T细胞的扩增和存活过程中，Env结合是否干扰CD134的正常细胞功能。这一部分将阐述Env-CD134相互作用如何在猫艾滋病的发病机制中做出贡献，这对于解释使用FIV作为艾滋病动物模型的研究具有重要意义。 最后，在目标3中，我们将调查在早期和晚期感染中是否存在具有不同生物学表型的病毒。初步观察表明，与来自有症状猫的病毒相比，来自无症状猫的病毒在体内具有不同的细胞嗜性、受体用途和生物学特性。此外，由于它们在体内实现了更高的病毒载量，并在早期感染中占主导地位，这些分离株很可能是在现场传播的菌株。由于到目前为止所研究的大多数分离株都来自表现出临床感染症状的动物，这些研究对于在这种广泛使用的小动物模型中未来试验新型疫苗和治疗方法的病毒选择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.