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.

R01CA100383

2003-04-08

2009-03-31