Identification of the gC1qR sites for the HIV-1 viral envelope protein gp41 and the HCV core protein: Implications in viral-specific pathogenesis and therapy.
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 gC1qR 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 gC1qR, 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 gC1qR and suppresses T cell proliferation resulting in a significantly diminished immune response, the gp41 employs gC1qR 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 gC1qR 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 gC1qR and 11 gC1qR deletion mutants. The results obtained from these studies have identified two major HCV core protein sites on a domain of gC1qR comprising of residues 144-148 and 196-202. Domain 196-202 in turn, is located in the last half of the larger gC1qR segment encoded by exons IV-VI (residues 159-282), which was proposed previously to contain the site for HCV core protein. The major gC1qR 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.
Center for Infection, Immunity and Disease Mechanisms, Biosciences, Brunel University, Uxbridge, UB8 3PH London, UK; The Departments of Medicine, Stony Brook University, Stony Brook, NY 11794, United States.
Lina
L
Pednekar
The Departments of Medicine, Stony Brook University, Stony Brook, NY 11794, United States.
Alisa
A
Valentino
The Departments of Medicine, Stony Brook University, Stony Brook, NY 11794, United States.
Yan
Y
Ji
The Departments of Pathology, Stony Brook University, Stony Brook, NY 11794, United States.
Nithin
N
Tumma
The Departments of Medicine, Stony Brook University, Stony Brook, NY 11794, United States.
Christopher
C
Valentino
Center for Infection, Immunity and Disease Mechanisms, Biosciences, Brunel University, Uxbridge, UB8 3PH London, UK; The Departments of Medicine, Stony Brook University, Stony Brook, NY 11794, United States; The Departments of Pathology, Stony Brook University, Stony Brook, NY 11794, United States; The Department of Laboratory Medicine, Memorial Sloan-Kettering Cancer Center (MSKCC), United States; The Department of Pathology, Weill-Cornell Medical College, NY, NY 10065, United States.
Adarsh
A
Kadoor
The Departments of Medicine, Stony Brook University, Stony Brook, NY 11794, United States.
Kinga K
KK
Hosszu
The Departments of Pathology, Stony Brook University, Stony Brook, NY 11794, United States.
Mahalakshmi
M
Ramadass
The Departments of Pathology, Stony Brook University, Stony Brook, NY 11794, United States.
Richard R
RR
Kew
Center for Infection, Immunity and Disease Mechanisms, Biosciences, Brunel University, Uxbridge, UB8 3PH London, UK.
Uday
U
Kishore
The Department of Laboratory Medicine, Memorial Sloan-Kettering Cancer Center (MSKCC), United States; The Department of Pathology, Weill-Cornell Medical College, NY, NY 10065, United States.
Ellinor I B
EI
Peerschke
The Departments of Medicine, Stony Brook University, Stony Brook, NY 11794, United States; The Departments of Pathology, Stony Brook University, Stony Brook, NY 11794, United States. Electronic address: Berhane.Ghebrehiwet@stonybrookmedicine.edu.
Berhane
B
Ghebrehiwet
D001665:Binding Sites / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000737:chemistry* / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D006801:Humans; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D051192:Receptors, Pattern Recognition / Q000737:chemistry* / Q000276:immunology; D020298:U937 Cells; D014758:Viral Core Proteins / Q000276:immunology*
C087299:C1QBP protein, human; D002352:Carrier Proteins; D015700:HIV Envelope Protein gp41; D024101:Mitochondrial Proteins; D051192:Receptors, Pattern Recognition; D014758:Viral Core Proteins; C514787:gp41 protein, Human immunodeficiency virus 1; C069130:nucleocapsid protein, Hepatitis C virus
HIV-1 gp41; Hepatitis C virus; PRR; gC1qR