Endogenous Retroviruses and the Immune Response to Pathogens

描述（由申请人提供）：大约8%的人类基因组是由逆转录病毒DNA的完整拷贝组成的。至少有一些内源性逆转录病毒被转录并翻译成蛋白质，但其功能后果尚不清楚。然而，内源性逆转录病毒编码许多与外源性逆转录病毒相同的基因，众所周知，外源性逆转录病毒可以操纵免疫系统，使慢性感染和疾病发生。例如，已知与β逆转录病毒小鼠乳腺肿瘤病毒（MMTV）（又名Mtvs）相关的内源性原病毒通过表达超抗原（Sag）影响小鼠的t细胞库。一种新的小鼠毒株BALB/Mtv-null已被开发出来，它与BALB/c小鼠同源，但缺乏内源性Mtv原病毒。我们已经证明，与亲本BALB/c菌株相比，mv -null小鼠对特定的病毒和细菌病原体具有更强的抵抗力，包括外源性MMTV， Friend小鼠白血病病毒和革兰氏阴性细菌，霍乱弧菌。尽管每种病原体的耐药机制可能不同，但初步数据表明，与BALB/c小鼠相比，Mtv-null小鼠的成熟不变自然杀伤T （iNKT）细胞数量增加。有趣的是，单个Mtv原病毒位于不同的小鼠染色体上，具有不同数量的基因，它们对iNKT表型或对病原体感染的抗性的贡献并不相同。对霍乱弧菌的易感性是由三种内源性Mtvs中的任何一种重组的，包括一个只编码Sag的Mtvs。然而，Sag-only Mtv原病毒仅部分重建mmtv诱导的乳腺肿瘤易感性，并没有增加Friend病毒病的易感性。另一方面，一个完整的原病毒，Mtv9，重建了对MMTV和Friend病毒的易感性。完整的MMTV原病毒编码Rem，这是一种与人内源性病毒K型（HERV-K） Rec蛋白相关的rev样蛋白。Rec已被证明与转录因子PLZF相互作用，PLZF控制iNKT细胞的功能和成熟。我们提出，由特定的鼠和人逆转录病毒编码的Rev-like蛋白通过PLZF和iNKT细胞控制对病原体的免疫反应。在第一个特定目标中，将开发表达rem或rec的转基因小鼠，并对其对iNKT细胞成熟和外源性逆转录病毒易感性的影响进行表征。在第二个特定目标中，原代胸腺细胞将被表达rem或rec的逆转录病毒转导，以确定它们对细胞表型和PLZF功能的影响。这些实验将增加我们对T细胞选择和分化以及对病原体的免疫反应的理解。这项提议的长期目标是开发治疗传染病的新方法。

DESCRIPTION (provided by applicant): Approximately 8% of the human genome is composed of integrated copies of retroviral DNA. At least some of the endogenous retroviruses are transcribed and translated into proteins, but the functional consequences are unclear. Nevertheless, endogenous retroviruses encode many of the same genes as exogenous retroviruses, which are known to manipulate the immune system to allow chronic infections and disease. For example, endogenous proviruses related to the betaretrovirus mouse mammary tumor virus (MMTV) (aka Mtvs) are known to affect the T-cell repertoire of mice through expression of superantigen (Sag). A novel mouse strain, BALB/Mtv-null, has been developed that is congenic to BALB/c mice, but lacks endogenous Mtv proviruses. We have shown that the Mtv-null mice are more resistant to specific viral and bacterial pathogens, including exogenous MMTV, Friend murine leukemia virus, and the gram- negative bacterium, Vibrio cholerae, compared to the parental BALB/c strain. Although the mechanism of resistance may not be the same for each pathogen, preliminary data indicate that Mtv-null mice have increased numbers of mature invariant natural killer T (iNKT) cells compared to those of BALB/c mice. Interestingly, individual Mtv proviruses, which are located on different mouse chromosomes and have different numbers of genes, do not contribute equally to iNKT phenotype or resistance to pathogen infection. Susceptibility to V. cholerae is reconstituted by any one of three endogenous Mtvs, including one that encodes only Sag. Nevertheless, the Sag-only Mtv provirus only partially reconstitutes susceptibility to MMTV-induced mammary tumors, and does not increase susceptibility to Friend virus disease. On the other hand, a complete provirus, Mtv9, reconstitutes susceptibility to both MMTV and Friend virus. Complete MMTV proviruses encode Rem, a Rev-like protein related to the human endogenous virus type K (HERV-K) Rec protein. Rec has been shown to interact with the transcription factor, PLZF, which controls the function and maturation of iNKT cells. We propose that Rev-like proteins encoded by specific murine and human retroviruses control the immune response to pathogens through PLZF and iNKT cells. In the first specific aim, transgenic mice expressing either rem or rec will be developed and characterized for their effects on the maturation of iNKT cells and susceptibility to exogenous retroviruses. In the second specific aim, primary thymocytes will be transduced with retroviruses expressing either rem or rec to determine their effects on cellular phenotype and PLZF function. These experiments will increase our understanding of T- cell selection and differentiation as well as the immune response to pathogens. The long-term goal of this proposal is the development of new approaches for treatment of infectious disease.