NEW RETROVIRAL RECEPTORS/HOST RESISTANCES

直到最近，只有几个逆转录病毒的细胞受体被分子克隆和功能鉴定。然而，利用一种强大的新策略，我们最近从人类T淋巴细胞cDNA文库中克隆了新的受体，包括一个用于异向性和多向性宿主范围的小鼠白血病病毒（mlv）的共同受体（x受体），一个用于猫白血病病毒C型（FeLV-C）的受体（C受体），它导致猫中普遍存在的再生障碍性贫血，以及一个用于RD 114猫内源性病毒的r受体，它也介导狒狒内源性病毒（BaEV）的感染。禽网状内皮增生病毒（REV）和灵长类动物D型逆转录病毒引起严重的免疫缺陷，并被报道为人类艾滋病患者的机会性感染。此外，我们确定r受体是宽特异性中性氨基酸转运体BO， x受体参与Na+-磷酸盐共转运，c受体是转运体大MFS（主要促进剂超家族）的成员。这些发现和方法为提高对这些和其他高致病性逆转录病毒的认识提供了机会。我们建议：(i)从小鼠中分离X-， R-和C-受体同源物，并使用人-小鼠嵌合体和位点定向突变体来鉴定这些受体的活性位点和小鼠抵抗感染的机制。（ii）相反，利用密切相关的异向性和多向性MLV包膜糖蛋白的嵌合体和定点突变体来鉴定控制这些病毒对不同小鼠株的不同感染性的氨基酸。因此，在病毒和x受体的水平上确定这种异向性的基础。（三）克隆其他逆转录病毒的极其重要的细胞表面受体，包括FeLV-A。（iv）彻底分析X-、R-和C-受体的正常细胞功能。研究感染对这些功能的影响以及这些功能扰动的致病后果。利用这些功能信息来优化基因治疗的转导效率。这些调查建立在技术突破的基础上，将大大扩大我们对人类和动物逆转录病毒疾病以及宿主耐药机制的了解。

Until recently, only several cellular receptors for retroviruses had been molecularly cloned and functionally identified. However, using a powerful new strategy we recently cloned novel receptors from a human T lymphocyte cDNA library, including a common receptor (X-receptor) for xenotropic and polytropic host-range groups of murine leukemia viruses (MLVs), a receptor (C-receptor) for feline leukemia virus type C (FeLV-C), which causes prevalent aplastic amenias in cats, and the R-receptor for RD 114 feline endogenous virus that also mediates infections by baboon endogenous virus (BaEV), avian reticuloendotheliosis virus (REV) and the primate type D retroviruses that cause severe immunodeficiencies and have been reported as an opportunistic infection in a human patient with AIDS. In addition, we determined that the R-receptor is the broad specificity neutral amino acid transporter BO, that the X-receptor is involved in Na+-phosphate cotransport, and that the C-receptor is a member of the large MFS (major facilitator superfamily) of transporters. These discoveries and methods provide opportunities for improved understanding of these and other highly pathogenic retroviruses. We propose: (i) Isolate X-, R-, and C- receptor homologues from mice and use human-mouse chimeras and site-directed mutants to identify active sites in these receptors and the mechanisms for murine resistances to infections. (ii) Conversely, use chimeras and site-directed mutants of closely related xenotropic and polytropic MLV envelope glycoproteins to identify amino acid(s) that control the differential infectivity of these viruses for various strains of mice. Thereby, identify the basis for this xenotropism at the levels of both the virus and the X-receptor. (iii) Clone critically important cell surface receptors for other retroviruses, including FeLV-A. (iv) Thoroughly analyze the normal cellular functions of the X-, R-, and C- receptors. Study the effects of infection on these functions and the pathogenic consequences of these functional perturbations. Use this functional information to optimize transduction efficiencies for gene therapy. These investigations build on a technological breakthrough and will substantially expand our understanding of human and animal retroviral diseases and of host resistance mechanisms.