Polymorphisms of the cell surface receptor control mouse susceptibilities to xenotropic and polytropic leukemia viruses
Polymorphisms of the cell surface receptor control mouse susceptibilities to xenotropic and polytropic leukemia viruses
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DOI：
10.1128/jvi.73.11.9362-9368.1999
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发表时间：
1999-11-01
影响因子：
5.4
通讯作者：
Kabat, D
中科院分区：
文献类型：
--
作者：
Marin, M;Tailor, CS;Kabat, D
小鼠品系对异嗜性和嗜多性小鼠白血病病毒（分别为X-MLV和P-MLV）的不同亲和性了解甚少，但可能涉及多种机制。最近的证据表明，这些病毒使用共同的细胞表面受体（X受体）感染人类细胞。我们描述的X-受体cDNA的特性与不同的序列克隆从活的实验室和野生品系的小鼠和仓鼠和水貂。这些cDNA在抗性细胞中的表达赋予了对天然感染cDNA来源动物的相同病毒的亲和性。因此，实验室小鼠（瑞士国立卫生研究院）X-受体赋予对P-MLV的易感性，但不赋予对X-MLV的易感性，而来自人、水貂和几种野生小鼠的那些则赋予对P-MLV的易感性。（Mus dunni、SC-1细胞和Mus spretus）介导的X-MLV和P-MLV感染。相反，来自抗性小鼠品系Mus castaneus和来自仓鼠的X受体作为病毒受体是无活性的，这些结果表明，X-受体多态性是小鼠对逆转录病毒X-MLV/P-MLV家族成员耐药的主要原因，并且是实验室小鼠中X-MLV异向性的原因。通过定点突变，我们取代M，Dunni和NM瑞士小鼠的X-受体之间的序列。MII Swiss蛋白包含两个关键差异（假定细胞外环3 [ECL 3]中的K500 E和ECL 4中的T582缺失），这两个差异都是阻断X-MLV感染所需的。因此，NIH Swiss蛋白中的单个反向突变赋予X-MLV易感性。此外，在中国仓鼠卵巢细胞中表达X-MLV包膜糖蛋白可有效干扰由含有K500和/或T582的X受体介导的X-MLV和P-MLV感染，但对由缺乏这些氨基酸的X受体介导的P-MLV感染无影响。相反，P-MLV（MCP 247）包膜糖蛋白的中度表达不会引起实质性干扰，表明X-MLV和P-MLV糖蛋白对X受体介导的感染无干扰。我们得出结论，P-MLV已经适应利用缺乏K500和T582的X受体，这种适应的惩罚是干扰重复感染的能力降低。由于干扰失败是几种异常致病性逆转录病毒的标志，我们认为它有助于P-MLV诱导的疾病。
The differential susceptibilities of mouse strains to xenotropic and polytropic murine leukemia viruses (X-MLVs and P-MLVs, respectively) are poorly understood but may involve multiple mechanisms. Recent evidence has demonstrated that these viruses use a common cell surface receptor (the X-reccptor) for infection of human cells. We describe the properties of X-receptor cDNAs with distinct sequences cloned from live laboratory and wild strains of mice and from hamsters and minks. Expression of these cDNAs in resistant cells conferred susceptibilities to the same viruses that naturally infect the animals from which the cDNAs were derived. Thus, a laboratory mouse (NIH Swiss) X-receptor conferred susceptibility to P-MLVs but not to X-MLVs, whereas those from humans, minks, and several wild mice (Mus dunni, SC-1 cells, and Mus spretus) mediated infections by both X-MLVs and P-MLVs, In contrast, X-receptors from the resistant mouse strain Mus castaneus and from hamsters were inactive as viral receptors, These results suggest that X-receptor polymorphisms are a primary cause of resistances of mice to members of the X-MLV/P-MLV family of retroviruses and are responsible for the xenotropism of X-MLVs in laboratory mice. By site-directed mutagenesis, we substituted sequences between the X-receptors of M, dunni and NM Swiss mice. The MII Swiss protein contains two key differences (K500E in presumptive extracellular loop 3 [ECL 3] and a T582 deletion in ECL 4) that are both required to block X-MLV infections. Accordingly, a single inverse mutation in the NIH Swiss protein conferred X-MLV susceptibility. Furthermore, expression of an X-MLV envelope glycoprotein in Chinese hamster ovary cells interfered efficiently with X-MLV and P-MLV infections mediated by X-receptors that contained K500 and/or T582 but had no effect an P-MLV infections mediated by X-receptors that lacked these amino acids. In contrast, moderate expression of a P-MLV (MCP247) envelope glycoprotein did not cause substantial interference, suggesting that X-MLV and P-MLV glycoproteins interfere nonreciprocally with X-receptor-mediated infections. We conclude that P-MLVs have become adapted to utilize X-receptors that lack K500 and T582, A penalty for this adaptation is a reduced ability to interfere with superinfection. Because failure of interference is a hallmark of several exceptionally pathogenic retroviruses, we propose that it contributes to P-MLV-induced diseases.