Receptor usage and pathogenicity of feline lentiviruses

该项目的总体目标是确定猫慢病毒的细胞受体，并研究病毒-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是家猫的猫免疫缺陷病毒（FIV）慢病毒的主要（如果不是唯一的话）共受体。在家猫中，FIV感染引起一种免疫缺陷综合征，类似于感染HIV的人类的艾滋病。在拟议的研究中，我们将询问受体的使用是否决定了猫慢病毒在家养猫和非家养猫中的致病性，就像灵长类慢病毒系统中受体的使用和致病性所假设的那样。一些证据表明，FIV原代菌株除了需要CXCR-4外，还需要另一种细胞表面分子（可能类似于HIV受体CD4）的共表达，才能感染所有靶细胞。目的1将确定FIV是否利用CXCR-4以外的主要受体感染猫细胞。我们将使用逆转录病毒伪型筛选cDNA文库，以寻找其他受体和/或共受体，并对分子的功能进行表征。目的2将检查受体使用和致病性之间的联系。我们将询问受体的使用是否在猫科慢病毒分离株中有所不同，即：(a)在实验研究中被定性为致病性与非致病性的分离株；(b)从无症状和有症状的自然感染猫身上获得的分离物；(c)在实验研究中通过不同途径传播的分离株。目的3将研究非家养猫和家养猫的慢病毒是否使用不同的病毒受体和普通的病毒受体。非家猫身上的慢病毒似乎比家猫身上的FIV更古老，更适应它们的宿主物种。我们将研究受体的使用是否是宿主适应的决定因素。这些研究将阐明猫慢病毒的细胞受体，确定受体使用的变化是否与致病性有关，并预测FIV/家猫和HIV/人受体病毒的未来进化结果。

The overall aim of this project is to identify the cellular receptor(s) for the feline lentiviruses and 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 is the major, if not sole, co-receptor for the feline immunodeficiency virus (FIV) lentivirus of the domestic cat. In the domestic cat, FIV infection induces an immunodeficiency syndrome similar to AIDS in HIV- infected humans. In the proposed studies, we will ask whether receptor usage determines pathogencity of feline lentiviruses in domestic vs. non-domestic cats as is postulated for receptor usage and pathogenicity in primate lentiviral systems. Several lines of evidence suggest that primary strains of FIV require the co-expression of another cell surface molecule (perhaps analogous to the HIV receptor CD4) in addition to CXCR-4 in order to infect all target cells. Aim 1 will determine whether FIV utilizes a primary receptor beside CXCR-4 for infection of feline cells. We will use retroviral pseudotypes to screen cDNA libraries for additional receptor(s) and/or co- receptors and the function of the molecule(s) will be characterised. Aim 2 will examine the link between receptor-usage and pathogenicity. We will ask whether receptor usage varies among feline lentivirus isolates, i.e.: (a) isolates characterized as pathogenic vs. non-pathogenic in experimental studies; (b) isolates obtained from asymptomatic vs. symptomatic naturally infected cats; and (c) isolates transmitted via different routes in experimental studies. Aim 3 will investigate whether non-domestic vs. domestic cat lentiviruses use different vs. common viral receptors. The lentiviruses of the non-domestic cats appear to be more ancient and more adapted to their host species than is FIV to the domestic cat. We will investigate whether receptor-usage is a determinant of host-adaptation. These studies will elucidate the cellular receptor(s) for the feline lentiviruses, determine whether changes in receptor usage relate to pathogenicity, and forecast the future of both FIV/domestic cat and HIV/human receptor-virus evolutionary outcomes.