Identification of the gene controlling murine retrovirus in YBR mice

摘要 对病毒感染的不同反应受到宿主基因构成的影响。结果, 人类对病毒感染的敏感度差别很大，有些人能抵抗很强的病毒。 病原体，如逆转录病毒、人类免疫缺陷病毒(HIV)。遗传抗性的研究进展 人类群体中的逆转录病毒非常复杂，很难分析出强大的抗病毒药物。 在开发疗法和疫苗时可以利用的效应机制。然而， 近交系小鼠对病毒感染的易感性的差异使小鼠成为治疗 定位机制和驱动哺乳动物对逆转录病毒的易感性和抵抗力的基因。外源 小鼠乳腺肿瘤病毒(MMTV)是一种经粘膜传播的逆转录病毒模型。这个 病毒是通过哺乳幼崽肠道中的乳汁获得的，并通过 淋巴细胞，在几个周期的再次感染/重新整合后，它会导致乳腺肿瘤。 对外源性MMTV感染和随后的乳腺肿瘤发生的易感性在不同的人之间有很大的差异 不同的小鼠品系，从绝对耐药到高度敏感。小鼠对MMTV具有抵抗力 YBR/EI(YBR)株被病毒感染，但不会发展为乳腺肿瘤，产生降低的病毒滴度， 并在连续的世代中有效地消除病原体。我们在初步研究中发现， YBR小鼠独特的病毒控制机制与抗病毒抗体、病毒特异性CD8+无关 细胞毒性T淋巴细胞、自然杀伤(NK)细胞和NK T细胞，但依赖于Thy1+淋巴样细胞。 此外，病毒的限制是由单个显性基因控制的，我们称之为病毒衰减。 滴度(AVT)，并已定位到18号染色体。利用遗传研究和计算分析，我们将 找出导致这一非凡效应机制的基因。

Abstract Differential responses to viral infections are influenced by the genetic makeup of the host. As a result, sensitivity of humans to viral infections varies considerably, with some individuals withstanding strong viral pathogens, such as the retrovirus, human immunodeficiency virus (HIV). Studies of inherited resistance to retroviruses in human populations are enormously complicated, making it difficult to dissect strong antiviral effector mechanisms that can be taken advantage of when developing therapeutics and vaccines. However, the variations in the susceptibility of inbred mice to viral infections make the mouse an excellent model for mapping mechanisms and genes driving mammalian susceptibility and resistance to retroviruses. Exogenous mouse mammary tumor virus (MMTV) represents a well-studied model of mucosally transmitted retrovirus. The virus is acquired through the milk in the gut of suckling pups and is passed to the mammary glands by lymphocytes, where it induces mammary gland tumors after several cycles of re-infection/re-integration. Susceptibility to exogenous MMTV infection and subsequent mammary tumorigenesis differs drastically among different mouse strains, ranging from absolute resistance to high susceptibility. Mice from the MMTV-resistant YBR/Ei (YBR) strain become virus-infected, but do not develop mammary tumors, produce reduced virus titers, and efficiently eliminate the pathogen in successive generations. In our preliminary studies we found that the unique mechanism of virus control in YBR mice is unrelated to anti-virus antibodies (Abs), virus-specific CD8+ cytotoxic T lymphocytes, natural killer (NK) cells, and NK T cells, but depends on Thy1+ lymphoid cells. Moreover, the virus restriction is controlled by a single, dominant locus, which we named attenuation of virus titers (avt) and have mapped to chromosome 18. Using genetic studies and computational analyses, we will identify the gene responsible for this remarkable effector mechanism.