Subversion of Innate Immune Response by Retroviruses

描述（由申请人提供）：先天免疫toll样受体（TLR）在微生物感染检测中起着至关重要的作用。对保守的病原体相关分子模式（PAMPs）的特异性允许TLR蛋白检测病原体的存在并诱导先天和随后的适应性抗微生物免疫反应的激活。病毒，像细菌和真菌一样，遇到先天和适应性免疫系统，因此，进化到逃避先天和适应性免疫反应。有些病毒甚至利用免疫系统的基本特性，为了自己的利益而破坏它们。我们发现小鼠乳腺肿瘤病毒（MMTV）通过颠覆先天免疫而独特地进化以逃避适应性免疫反应。我们的模型使用C3H/HeJ和C3H/HeN亚株，它们在50多年前从感染外源性野生型MMTV（C3H）的祖菌株C3H/St分化而来。随着时间的推移，野生型MMTV（C3H）从C3H/HeJ株中完全消失，取而代之的是野生型MMTV（C3H）和内源性Mtvl之间的病毒重组。相比之下，野生型MMTV（C3H）在C3H/HeN小鼠中持续存在。我们用野生型MMTV（C3H）感染无MMTV的C3H/HeJ小鼠，重现了与MMTV（HeJ）相似的重组病毒的选择和MMTV（C3H）的缺失。这些结果清楚地表明C3H/HeJ小鼠存在对野生型MMTV（C3H）的选择性压力。这种选择压力可能是由抗病毒适应性免疫反应决定的，并受到C3H/HeJ小鼠中发现的Tlr4基因突变等位基因的影响。我们假设MMTV（C3H）与TLR4的相互作用是病毒逃避抗病毒免疫应答的必要条件。相反，在C3H/HeJ小鼠中，突变的TLR4使病毒无法避免适应性免疫应答的攻击，导致免疫逃逸重组MMTV（HeJ）的选择。据我们所知，这是第一个病原体为了自己的利益而破坏先天免疫的例子。我们建议：1)研究先天免疫反应在逆转录病毒传播中的作用；2)确定控制MMTV复制的免疫机制。

DESCRIPTION (provided by applicant): Innate immunity Toll-like receptors (TLR) have a crucial role in the detection of microbial infection. Specificity for conserved pathogen-associated molecular patterns (PAMPs) allows TLR proteins to detect the presence of pathogens and to induce the activation of innate and subsequently, adaptive anti-microbial immune responses. Viruses, like bacteria and fungi, encounter innate and adaptive immune systems, and thus, have evolved to evade both the innate and adaptive immune responses. Some viruses even take advantage of fundamental properties of the immune system, and subvert them for their own benefit. We found that mouse mammary tumor virus (MMTV) has uniquely evolved to evade the adaptive immune response via subversion of innate immunity. Our model uses the C3H/HeJ and C3H/HeN substrains, which diverged more than 50 years ago from a progenitor strain, C3H/St, infected with exogenous wild-type MMTV(C3H). Over time wild-type MMTV(C3H) was completely lost from the C3H/HeJ strain and was replaced with a virus recombinant between wild-type MMTV(C3H) and an endogenous Mtvl. In contrast, wild-type MMTV(C3H) persists in C3H/HeN mice. We were able to reproduce the selection of recombinant viruses similar to MMTV(HeJ) and the loss of MMTV(C3H) by infecting MMTV-free C3H/HeJ mice with wild-type MMTV(C3H). These results clearly suggested that a selective pressure against wild-type MMTV(C3H) exists in C3H/HeJ mice. This selective pressure was likely determined by anti-virus adaptive immune response and influenced by the mutant allele of the Tlr4 gene found in C3H/HeJ mice. We hypothesize that MMTV(C3H) interaction with TLR4 is necessary for the virus to evade the anti-virus immune response. In contrast, mutant TLR4 in C3H/HeJ mice renders the virus unable to avoid attack by the adaptive immune response, resulting in the selection of the immune escape recombinant MMTV(HeJ). To our knowledge this is the first example where a pathogen subverts the innate immunity for its own benefit. We propose to: 1) investigate the role of the innate immune response in retrovirus transmission, and 2) identify the immune mechanism which controls MMTV replication.