NIH, NIAID, LMM, Bldg. 4, Room 329, 4 Center Drive MSC 0460, Bethesda, MD 20892-0460.
J Virol. 2010 Nov;84(22):11970-80. doi: 10.1128/JVI.01549-10. Epub 2010 Sep 15.
Genetic conflicts between retroviruses and their receptors result in the evolution of novel host entry restrictions and novel virus envelopes, and such variants can influence trans-species transmission. We screened rodents and other mammals for sequence variation in the Xpr1 receptor for the mouse xenotropic or polytropic mouse leukemia viruses (X-MLVs or P-MLVs, respectively) of the gammaretrovirus family and for susceptibility to mouse-derived X/P-MLVs and to XMRV (xenotropic murine leukemia virus-related virus), an X-MLV-like virus isolated from humans with prostate cancer and chronic fatigue syndrome. We identified multiple distinct susceptibility phenotypes; these include the four known Xpr1 variants in Mus and a novel fifth Xpr1 gene found in Mus molossinus and Mus musculus. We describe the geographic and species distribution of the Mus Xpr1 variants but failed to find the X-MLV-restrictive laboratory mouse allele in any wild mouse. We used mutagenesis and phylogenetic analysis to evaluate the functional contributions made by constrained, variable, and deleted residues. Rodent Xpr1 is under positive selection, indicating a history of host-pathogen conflicts; several codons under selection have known roles in virus entry. All non-Mus mammals are susceptible to mouse X-MLVs, but some restrict other members of the X/P-MLV family, and the resistance of hamster and gerbil cells to XMRV indicates that XMRV has unique receptor requirements. We show that the hypervariable fourth extracellular XPR1 loop (ECL4) contains three evolutionarily constrained residues that do not contribute to receptor function, we identify two novel residues important for virus entry (I579 and T583), and we describe a unique pattern of ECL4 variation in the three virus-restrictive Xpr1 variants found in MLV-infected house mice; these mice carry different deletions in ECL4, suggesting either that these sites or loop size affects receptor function.
逆转录病毒与其受体之间的遗传冲突导致新的宿主进入限制和新的病毒包膜的进化，并且这种变体可以影响跨物种传播。我们筛选了啮齿动物和其他哺乳动物，以检测 Xpr1 受体的序列变异，该受体是γ逆转录病毒家族的鼠嗜性或多嗜性鼠白血病病毒（X-MLV 或 P-MLV），以及对鼠衍生的 X/P-MLV 和 XMRV（嗜性鼠白血病病毒相关病毒）的易感性，XMRV 是一种从患有前列腺癌和慢性疲劳综合征的人类中分离出的 X-MLV 样病毒。我们确定了多种不同的易感性表型；这些包括 Mus 中的四个已知 Xpr1 变体和在 Mus molossinus 和 Mus musculus 中发现的新型第五个 Xpr1 基因。我们描述了 Mus Xpr1 变体的地理和物种分布，但在任何野生小鼠中都没有发现 X-MLV 限制的实验室小鼠等位基因。我们使用诱变和系统发育分析来评估受限制、可变和缺失残基的功能贡献。啮齿动物 Xpr1 受到正选择，表明存在宿主-病原体冲突的历史；选择的几个密码子在病毒进入中具有已知作用。所有非 Mus 哺乳动物均易感染鼠 X-MLV，但有些限制 X/P-MLV 家族的其他成员，仓鼠和沙鼠细胞对 XMRV 的抗性表明 XMRV 具有独特的受体要求。我们表明，超变的第四细胞外 XPR1 环（ECL4）包含三个进化上受限制的残基，这些残基对受体功能没有贡献，我们确定了两个对病毒进入很重要的新残基（I579 和 T583），并且我们描述了在感染 MLV 的家鼠中发现的三种病毒限制 Xpr1 变体中独特的 ECL4 变异模式；这些小鼠在 ECL4 中携带不同的缺失，这表明这些位点或环大小会影响受体功能。
