Journal
MOLECULAR IMMUNOLOGY
Volume 74, Issue -, Pages 18-26Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2016.03.016
Keywords
gC1qR; PRR; Hepatitis C virus; HIV-1 gp41
Categories
Funding
- NCI NIH HHS [P30 CA008748] Funding Source: Medline
- NIAID NIH HHS [R01 AI084178, R01 AI060866] Funding Source: Medline
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A substantial body of evidence accumulated over the past 20 years supports the concept that gC1qR is a major pathogen-associated pattern recognition receptor (PRR). This conclusion is based on the fact that, a wide range of bacterial and viral ligands are able to exploit gClqR to either suppress the host's immune response and thus enhance their survival, or to gain access into cells to initiate disease. Of the extensive array of viral ligands that have affinity for gClqR, the HIV-1 envelope glycoprotein gp41, and the core protein of hepatitis C virus (HCV) are of major interest as they are known to contribute to the high morbidity and mortality caused by these pathogens. While the HCV core protein binds gClqR and suppresses T cell proliferation resulting in a significantly diminished immune response, the gp41 employs gClqR to induce the surface expression of the NK cell ligand, NKp44L, on uninfected CD4+ T cells, thereby rendering them susceptible to autologous destruction by NKp44 receptor expressing NK cells. Because of the potential for the design of peptide-based or antibody-based therapeutic options, the present studies were undertaken to define the gClqR interaction sites for these pathogen-associated molecular ligands. Employing a solid phase microplate-binding assay, we examined the binding of each viral ligand to wild type gClqR and 11 gClqR deletion mutants. The results obtained from these studies have identified two major HCV core protein sites on a domain of gClqR comprising of residues 144-148 and 196-202. Domain 196-202 in turn, is located in the last half of the larger gClqR segment encoded by exons IV-VI (residues 159-282), which was proposed previously to contain the site for HCV core protein. The major gClqR site for gp41 on the other hand, was found to be in a highly conserved region encoded by exon IV and comprises of residues 174-180. Interestingly, gC1qR residues 174-180 also constitute the cell surface binding site for soluble gC1qR (sgC1qR), which can bind to the cell surface in an autocrine/paracrine manner via surface expressed fibrinogen or other membrane molecules. The identification of the sites for these viral ligands should therefore provide additional targets for the design of peptide-based or antigen-based therapeutic strategies. (C) 2016 Elsevier Ltd. All rights reserved.
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