TLR7-independent control of retroviral infection

ABSTRACT Development of effective immune responses against any pathogen requires efficient activation of the innate immune system followed by induction of an appropriate adaptive immune response using specific signaling pathways tailored to each infection. The sole innate immune receptor implicated in the induction of adaptive immunity to retroviral infection is Toll like receptor 7 (TLR7). We have found that germinal center responses, neutralizing antibody production, and clearance of murine leukemia virus (MLV) infection in BALB.J and C57BL/6N (B6N) mice occurs in the absence of TLR7 signaling. This suggests that a previously unknown alternative sensing pathway exists for the activation of protective immune responses upon retroviral infection. Genetic crosses indicate that the ability to control retroviral infection in the absence of TLR7 signaling is determined by the same recessive mechanism in both B6N and BALB.J mice, suggesting that TLR7-independent responses do not result from a gain-of-function of an alternative pattern recognition receptor. Additionally, we observed that TLR7-deficient BALB.J mice produce neutralizing antibodies against mouse mammary tumor virus (MMTV) infection, indicating that this alternative sensing pathway is active against retroviruses of multiple genera. Finally, we determined that the alternative sensing pathway is also independent of both MyD88 and STING signaling. The ability of mice of two genetic backgrounds to control retroviral infection in the absence of TLR7 signaling provides a valuable tool for the identification of a novel mechanism of retrovirus control. The dissection of this pathway has the potential to alter our understanding of the requirements for the stimulation of antigen-specific neutralizing immunity. Significance Statement Innate immune sensors are required for induction of pathogen-specific immune responses, and the development of novel vaccines requires an understanding of the basic mechanisms by which the immune system detects and responds to pathogens. While multiple innate immune receptors have been implicated in the sensing of retroviral infection, only Toll-like receptor 7 (TLR7) has been found to upregulate adaptive immune responses. Here, we demonstrate that an additional TLR7-independent mechanism for the activation of antiretroviral antibody responses is present in inbred mice from two genetic backgrounds. This finding has implications for the selection of mouse models for the study of antiviral immune responses and has the potential to alter our understanding of the requirements for the stimulation of antigen-specific neutralizing immunity.