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(S)，并研究病毒与受体的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)共同受体。在家猫中，FIV感染会导致一种免疫缺陷综合征，类似于艾滋病毒感染者的艾滋病。在拟议的研究中，我们将询问受体的使用是否决定了猫慢病毒在家猫和非家猫中的致病性，就像在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的主要毒株除了CXCR-4外，还需要另一种细胞表面分子(可能类似于HIV受体CD4)的共同表达，才能感染所有的靶细胞。目的1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来筛选额外受体(S)和/或辅助受体的cDNA库，并对分子(S)的功能进行表征。目标2将研究受体使用和致病性之间的联系。我们将询问猫慢病毒分离株的受体使用情况是否有所不同，即：(A)在实验研究中被描述为致病和非致病的分离株；(B)从无症状和有症状的自然感染的猫身上获得的分离株；以及(C)在实验研究中通过不同途径传播的分离株。目标3将调查非家养和家养猫慢病毒是否使用不同的与常见的病毒受体。与家猫的FIV相比，非家猫的慢病毒似乎更古老，更适应它们的宿主物种。我们将调查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(S)，确定受体使用的变化是否与致病性有关，并预测未来FIV/家猫和艾滋病毒/人类受体病毒的进化结果。

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.