Most retroviral infections result in indefinite viral persistence with an undetectable or inefficient anti-virus immune response. Poor immune reactivity has made the elucidation of protective anti-retroviral pathways an incredibly arduous endeavor. There are, however, rare individuals capable of mounting a potent anti-retroviral immune response, and the study of these individuals has allowed dissection of the protective responses. For example, some Human Immunodeficiency Virus (HIV)-infected individuals termed `long-term or elite non-progressors' are able to initiate and maintain robust anti-viral responses via specific genetic mechanisms. Whereas studies of retrovirus resistance in humans are complicated by genetic diversity, inbred mice offer an experimentally tractable alternative for mapping mammalian resistance and susceptibility genes. Two examples of such models are mice from the C57BL/6J (B6) and I/LnJ strains, which successfully constrain retroviruses via production of neutralizing antibody (Ab) responses. Whereas the gene responsible for controlling Murine Leukemia Virus (MuLV) in B6 mice has been identified (apobec3), the gene underlying retrovirus resistance in I/LnJ mice remains unknown. We have previously described a virus infectivity controller 1 (vic1) locus, containing a recessive retrovirus resistance-conferrng gene in I/LnJ mice and mapped it to Chromosome 17. Unlike apobec3, vic1 confers resistance to two distinct retroviruses, MuLV and Mouse Mammary Tumor Virus (MMTV). Although an initial poly-isotypic anti-virus immune response is observed in susceptible mice, it is short-lived and does not class-switch to an IgG2a response as it does in resistant ILn/J mice. Unlike virus-susceptible mice, I/LnJ mice infected with either retrovirus produce virus-neutralizing Abs, sustain this response throughout their life, and prevent infection of progeny by coating secreted virions with anti-virus Abs. Using congenic and bacterial artificial chromosome (BAC) transgenic approaches, we fine- mapped the vic1 locus to a 32.9Kb region between 34,211,575 -34,244,528 Kbs. A non-classical major histocompatibility class II (MHCII) gene, H2-Ob (Ob) mapped within the region was identified as the gene encoding for Vic1 by virtue of its known function, unique polymorphism and a phenotype rescue experiment. Peptide loading of MHCII molecules in the endosomes of antigen presenting cells (APCs) is catalyzed by H2-M. The evolutionally conserved Ob encodes the O? molecule that together with O?, comprises the heterodimeric H2-O molecule. H2-O is a MHCII mimic and binds to H2-M thereby inhibiting MHCII peptide presentation. The biological relevance of H2-O inhibition of MHCII peptide loading is poorly understood. Importantly, the role of H2-O during the immune response against any pathogen is completely unexplored. The successful completion of aims described in this application will reveal the mechanism by which the MHC-like molecule, H2-O controls the immune response to retroviruses.
Elucidation of the mechanism by which a non-classical major histocompatibility II gene, Ob mediates a retrovirus protective antibody responses will help to improve vaccination protocols and will enable natural antibody responses in infected individuals.
|Denzin, Lisa K; Khan, Aly A; Virdis, Francesca et al. (2017) Neutralizing Antibody Responses to Viral Infections Are Linked to the Non-classical MHC Class II Gene H2-Ob. Immunity 47:310-322.e7|