Immunogenicity of the Extracellular Domains of C-C Chemokine Receptor 5 and the In Vitro Effects on Simian Immunodeficiency Virus or HIV Infectivity

• Published in: The Journal of immunology (1950) 2001-06, Vol.166 (12), p.7446-7455
• Main Authors: Lehner, Thomas, Doyle, Carl, Wang, Yufei, Babaahmady, Kaboutar, Whittall, Trevor, Tao, Louisa, Bergmeier, Lesley, Kelly, Charles
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal - pharmacology; Antiviral Agents - pharmacology; Baculoviridae - genetics; Baculoviridae - immunology; CCR5 protein; Cell Line; Cell Membrane - immunology; Cell Membrane - metabolism; Cells, Cultured; Chemokines, CC - biosynthesis; Chemokines, CC - immunology; Epitope Mapping; Epitopes, B-Lymphocyte - analysis; Epitopes, T-Lymphocyte - analysis; Extracellular Space - immunology; HIV-1 - immunology; Human immunodeficiency virus; Humans; Immune Sera - pharmacology; Immunoglobulin A - blood; Immunoglobulin G - blood; Immunoglobulin G - pharmacology; Injections, Intramuscular; Lymphocyte Activation - immunology; Lymphoid Tissue - cytology; Lymphoid Tissue - immunology; Macaca mulatta; Molecular Sequence Data; Peptide Fragments - administration & dosage; Peptide Fragments - chemical synthesis; Peptide Fragments - genetics; Peptide Fragments - immunology; Protein Structure, Tertiary - genetics; Receptors, CCR5 - administration & dosage; Receptors, CCR5 - biosynthesis; Receptors, CCR5 - genetics; Receptors, CCR5 - immunology; Simian immunodeficiency virus; Simian Immunodeficiency Virus - immunology; Simian Immunodeficiency Virus - physiology; Spodoptera - genetics; Spodoptera - immunology; T-Lymphocytes - immunology; T-Lymphocytes - virology; Transfection; Up-Regulation - immunology; Virus Replication - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.12.7446

The C-C chemokine receptor CCR5 serves an important function in chemotaxis of lymphocytes, monocytes, and dendritic cells. CCR5 is also the major coreceptor in most macrophage-tropic HIV-1 infections. Immunization of rhesus macaques with a baculovirus-generated CCR5 construct or peptides derived from the sequences of the four extracellular domains of CCR5 elicited IgG and IgA Abs, inhibition of SIV replication, and CD4+ T cell proliferative responses to three of the extracellular domains of CCR5. The immune sera reacted with cell surface CCR5 expressed on HEK 293 cells. T and B cell epitope mapping revealed major and minor T and B cell epitopes in the N-terminal, first, and second loops of CCR5. The three C-C chemokines, RANTES, macrophage-inflammatory protein-1alpha, and macrophage-inflammatory protein-1beta, were up-regulated by immunization with the CCR5-derived peptides, and the cell surface expression of CCR5 was decreased. The CCR5 Abs were complementary to the C-C chemokines in inhibiting HIV replication in vitro. Immunization with the four extracellular domains of CCR5 suggests that three of them are immunogenic, with maximal T cell responses being elicited by the second loop peptide. However, maximal Abs to the cell surface CCR5 or viral inhibitory Abs in vitro were induced by the N-terminal peptide. Up-regulation of the three C-C chemokines and down-modulation of cell surface CCR5 were elicited by the second loop, N-terminal, and first loop peptides. The data suggest that a dual mechanism of C-C chemokines and specific Abs may engage and down-modulate the CCR5 coreceptors and prevent in vitro HIV or SIV replication.