Subversion of Innate Immune Response by Retroviruses

性状（由申请方提供）：先天免疫Toll样受体（TLR）在微生物感染检测中具有关键作用。对保守的病原体相关分子模式（PAMP）的特异性允许TLR蛋白检测病原体的存在并诱导先天性和随后的适应性抗微生物免疫应答的激活。病毒，如细菌和真菌，遇到先天和适应性免疫系统，因此，已经进化到逃避先天和适应性免疫反应。一些病毒甚至利用免疫系统的基本特性，并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）已经独特地进化到通过破坏先天免疫来逃避适应性免疫应答。我们的模型使用C3 H/HeJ和C3 H/HeN亚株，其在50多年前从感染外源性野生型MMTV（C3 H）的祖株C3 H/St分化。随着时间的推移，野生型MMTV（C3 H）从C3 H/HeJ毒株中完全丢失，并被野生型MMTV（C3 H）和内源性Mtvl之间的病毒重组体取代。相反，野生型MMTV（C3 H）在C3 H/HeN小鼠中持续存在。通过用野生型MMTV（C3 H）感染无MMTV的C3 H/HeJ小鼠，我们能够再现与MMTV（HeJ）相似的重组病毒的选择和MMTV（C3 H）的损失。这些结果清楚地表明，在C3 H/HeJ小鼠中存在针对野生型MMTV（C3 H）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C3 H/HeJ小鼠中发现的Tlr 4基因突变等位基因的影响。我们推测MMTV（C3 H）与TLR 4的相互作用是病毒逃避抗病毒免疫应答所必需的。相反，C3 H/HeJ小鼠中的突变型TLR 4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，这是病原体为了自身利益而破坏先天免疫的第一个例子。我们建议：1）研究先天免疫应答在逆转录病毒传播中的作用，和2）鉴定控制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.