Receptor usage and pathogenicity of feline lentiviruses

描述（由申请人提供）：该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基础上，证明CXCR-4和CD134分别是猫免疫缺陷病毒（FIV）的主要共受体和主要结合受体，FIV是家猫的慢病毒。在猫中，FIV感染引起免疫缺陷综合征，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，以及在感染的早期和晚期是否存在具有不同受体使用的病毒。

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.