In-vivo-tracking, immune control and autoimmunity in genetic models of murine endogenous retrovirus reactivation

艾滋病毒是过去几十年中最臭名昭著的新出现的传染病，仍在等待更有效的治疗或成功的疫苗接种。但逆转录病毒在进化过程中一直对哺乳动物构成威胁，最终通过所谓的内源性逆转录病毒(ERV)入侵人类和小鼠的基因组。尽管在人类中它们作为传染性逆转录病毒的功能仍有争议，但某些小鼠株可以表达ERV，类似于小鼠白血病病毒(MuLV)，并屈服于逆转录病毒诱导的疾病。最近，免疫学家已经证明，适应性(B细胞介导的抗体产生)或先天性免疫识别(核酸感知TLRs-3、-7和-9)的损害都会导致小鼠模型系统中无法控制的ERV介导的逆转录病毒血症。然而，免疫反应的复杂性以及与各种细胞内在抗逆转录病毒机制的潜在相互作用需要新的模型来破译逆转录病毒表达和免疫控制的基础。在这里，我们建议产生标记的MuLV，它表达荧光或荧光素酶标记，允许在体内检测传染性逆转录病毒或实验引入的生殖系编码的ERV的复活。这些模型结合先天免疫和获得性免疫，特别是B细胞反应对ERV识别和抑制的细胞和分子分析，可能有助于更好地理解逆转录病毒免疫相互作用的生物学一般。最后，我们将尝试建立一个遗传模型，解决逆转录病毒如何在体内打破自我耐受并诱导自身免疫的机制。

HIV is the most infamous new emerging infectious disease in the last decades, still awaiting more effective treatment or successful vaccination. But retroviruses have posed a constant threat to mammals during evolution, culminating in invasion of the human and mouse genome, by so-called endogenous retroviruses (ERVs). Although their functionality as infectious retroviruses is still debated in humans, certain mouse strains can express ERVs, similar to murine leukemia virus (MuLV) and succumb to retrovirus induced disease. Recently, immunologists have demonstrated that both the impairment of adaptive (B cell mediated antibody production) or innate immune recognition (nucleic-acid-sensing TLRs -3,-7 and -9) results in uncontrolled ERV mediated retroviral viremia in murine model systems. However, the complexity of the immune response and potential interactions with a variety of cell intrinsic anti-retroviral mechanism warrant new models deciphering the basics of retroviral expression and immune control. Here, we propose the generation of tagged MuLV, which express fluorescent- or luciferase markers, that allow the in vivo detection of infectious retroviruses or the resurrection of experimentally introduced germline encoded ERVs. These models, in conjunction with the cellular and molecular analysis of ERV recognition and inhibition by innate and adaptive immunity, in particular the B cell response, might allow a better understanding of the biology of retroviral immune interactions in general. Finally, we will try to generate a genetic model, which addresses a mechanism how retroviruses could break self-tolerance and induce autoimmunity in vivo.