Cloning of the vic1 gene, a novel retrovirus restriction factor

描述（由申请人提供）：逆转录病毒通过破坏宿主免疫反应在人类中引起致命疾病，如获得性免疫缺陷综合征和T细胞白血病。有大量证据表明，人类群体中的遗传变异会影响受感染个体的疾病结果。虽然研究人类群体中对逆转录病毒的遗传抗性非常复杂，但近交系小鼠对逆转录病毒感染的易感性的变化使小鼠成为绘制哺乳动物抗性和易感基因的极好模型。与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，它们已经进化出许多机制来避免被易感小鼠的免疫系统消除。然而，病毒不能在I/LnJ小鼠中复制，因为感染任一病毒的这些小鼠产生病毒中和抗体，在其整个生命中维持这种应答，并通过用抗病毒抗体包被分泌的病毒体来防止其后代的感染。我们建立了抗体介导的干扰病毒进入是唯一的因素抑制病毒传播的I/LnJ小鼠。在这两种系统中产生的病毒中和抗体需要IFN-γ，是独立的IL-12。这种独特的逆转录病毒耐药性遗传的I/LnJ小鼠的机制是由一个单一的隐性基因，病毒感染性控制器1（vic 1），映射到17号染色体的主要组织相容性位点以外的17.1 Mb区域控制。使用BALB/cJ小鼠同源的vic 1 I/LnJ基因座，我们发现，除了控制抗病毒的体液免疫反应，vic 1也影响生产的病毒特异性细胞毒性反应，防止疾病诱导的逆转录病毒。vic 1介导的抗性机制与已知的由对Friend病毒3（rfv 3）的抗性基因控制的对MuLV的抗性机制相似。然而，这两种抗性机制彼此明显不同，因为rfv 3基因已定位于染色体15，并赋予对MuLV的抗性，但不赋予对MMTV的抗性。因此，我们已经确定了一个独特的病毒抗性机制，控制对两个不同属的逆转录病毒的免疫力。我们建议定位克隆vic 1基因。阐明I/LnJ小鼠中逆转录病毒抗性的机制具有根本的重要性，并且最终将导致增加关于人类对病毒感染的易感性的变化的知识，以及开发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.