Cloning of the vic1 gene, a novel retrovirus restriction factor

描述(申请人提供)：逆转录病毒通过破坏宿主免疫反应而导致人类致命性疾病，如获得性免疫缺陷综合症和T细胞白血病。有大量证据表明，人类群体中的基因变异会影响受感染个体的疾病结局。虽然人类群体对逆转录病毒的遗传抵抗力的研究非常复杂，但近交系小鼠对逆转录病毒感染的易感性的差异使小鼠成为定位哺乳动物抵抗力和易感基因的极佳模型。和HIV一样，小鼠乳腺肿瘤病毒(MMTV)和小鼠白血病病毒(MuLV)也是逆转录病毒，它们进化了多种机制来避免被敏感小鼠的免疫系统消除。然而，这些病毒无法在I/LnJ小鼠身上复制，因为这些感染了这两种病毒的小鼠都会产生病毒中和抗体，并在其一生中保持这种反应，并通过将分泌的病毒粒子包裹上抗病毒抗体来防止其后代感染。我们证实，抗体介导的干扰病毒进入是抑制病毒在I/LnJ小鼠中传播的唯一因素。在这两个系统中产生病毒中和抗体需要干扰素-g，并且不依赖于IL-12。这种由I/LnJ小鼠遗传的独特的逆转录病毒耐药机制由一个单一的隐性基因控制，即病毒感染性控制器1(Vic1)，定位于17号染色体主要组织相容性基因外的17.1Mb区域。使用BALB/CJ小鼠的vic1I/LnJ基因座，我们发现，除了控制抗病毒体液免疫反应外，vic1还影响病毒特异性细胞毒反应的产生，以防止逆转录病毒诱导疾病。Vic1介导的抗性机制与已知的由Friend病毒3(Rfv3)基因控制的MuLV抗性机制相似。然而，这两种抗性机制显然是不同的，因为rfv3基因被定位在15号染色体上，对MuLV具有抗性，但对MMTV没有抗性。因此，我们已经确定了一种独特的病毒抵抗机制，它控制着对来自两个不同属的逆转录病毒的免疫。我们建议对vic1基因进行定位克隆。阐明I/LnJ小鼠对逆转录病毒的耐药性机制具有重要意义，最终将有助于增加对人类对病毒感染的易感性差异的了解，并开发出针对人类病毒和其他疾病的最有效的疫苗。

DESCRIPTION (provided by applicant): Retroviruses cause lethal diseases in humans such as acquired immunodeficiency syndrome and T-cell leukemia by defeating host immune responses. There is large body of evidence suggesting that genetic variations in the human population influence the disease outcome in infected individuals. While studies of inherited resistance to retroviruses in human populations are enormously complicated, the variations in the susceptibility of inbred mice to retroviral infections make the mouse an excellent model for mapping mammalian resistance and susceptibility genes. Like HIV, Mouse Mammary Tumor Virus (MMTV) and Murine Leukemia Virus (MuLV) are retroviruses that have evolved numerous mechanisms to avoid elimination by the immune systems of susceptible mice. However, the viruses fail to replicate in I/LnJ mice as these mice infected with either virus produce virus-neutralizing antibodies, sustain this response throughout their life, and prevent infection of their progeny by coating secreted virions with anti- virus antibodies. We established that antibody-mediated interference with viral entry is the sole factor inhibiting virus transmission in I/LnJ mice. Generation of virus-neutralizing Abs in both systems required IFN-g and was independent of IL-12. This unique mechanism of retroviral resistance inherited by I/LnJ mice is controlled by a single recessive gene, virus infectivity controller 1 (vic1), mapped to a 17.1 Mb region of Chromosome 17 outside the major histocompatibility locus. Using BALB/cJ mice congenic for the vic1 I/LnJ locus, we found that in addition to controlling the anti-virus humoral immune response, vic1 also influences the production of a virus specific cytotoxic response that prevents disease induction by the retroviruses. The vic1-mediated resistance mechanism bears a resemblance to the well-known resistance mechanism against MuLV controlled by the resistance to Friend virus 3 (rfv3) gene. However, the two resistance mechanisms are clearly different from one another, since the rfv3 gene has been mapped to Chromosome 15 and confers resistance to MuLV but not to MMTV. Thus, we have identified a unique virus resistance mechanism which controls immunity against retroviruses from two distinct genera. We propose to positional clone the vic1 gene. The elucidation of the mechanism of retrovirus resistance in I/LnJ mice is of fundamental importance and will ultimately lead to increased knowledge about variations in susceptibility to viral infections in humans and to development of the most effective vaccines against human viruses, and other diseases.