Cloning of the vic1 gene, a novel retrovirus restriction factor

描述（由申请人提供）：逆转录病毒通过击败宿主免疫反应，在人类中引起致命性疾病，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，人群中的遗传变异会影响受感染者的疾病结局。虽然人类群体对逆转录病毒的遗传抗性的研究非常复杂，但近亲繁殖的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性基因的绝佳模型。像HIV一样，小鼠乳腺肿瘤病毒（MMTV）和小鼠白血病病毒（MuLV）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，这两种病毒不能在I/LnJ小鼠体内复制，因为感染这两种病毒的小鼠都会产生病毒中和抗体，并在其一生中维持这种反应，并通过在分泌的病毒粒子上涂上抗病毒抗体来防止其后代感染。我们确定抗体介导的病毒进入干扰是抑制I/LnJ小鼠病毒传播的唯一因素。在这两种系统中产生病毒中和抗体都需要IFN-g，并且不依赖于IL-12。I/LnJ小鼠遗传的这种独特的逆转录病毒抗性机制是由一个单隐性基因控制的，病毒传染性控制因子1 (vic1)，定位于17号染色体的17.1 Mb区域，在主要组织相容性位点之外。利用BALB/cJ小鼠的vic1 I/LnJ基因，我们发现除了控制抗病毒体液免疫应答外，vic1还影响病毒特异性细胞毒性应答的产生，从而阻止逆转录病毒诱导的疾病。vic1介导的耐药机制与众所周知的由Friend病毒3 （rfv3）基因控制的MuLV耐药机制相似。然而，这两种抗性机制显然彼此不同，因为rfv3基因已被定位到第15号染色体上，并赋予对MuLV而不是MMTV的抗性。因此，我们已经确定了一种独特的病毒抗性机制，控制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小鼠中逆转录病毒耐药性的机制具有根本性的重要性，并将最终导致增加对人类病毒感染易感性变化的认识，并开发针对人类病毒和其他疾病的最有效疫苗。

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.