Immunogenicity of the extracellular domains of C-C chemokine receptor 5 and the in vitro effects on simian immunodeficiency virus or HIV infectivity.
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.
Lehner
T
T
Departments of. Immunobiology and Oral Medicine and Pathology, Guy's, King's & St. Thomas' Hospital Medical Schools, London, United Kingdom. thomas.lehner@kcl.ac.uk
Doyle
C
C
Wang
Y
Y
Babaahmady
K
K
Whittall
T
T
Tao
L
L
Bergmeier
L
L
Kelly
C
C
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D016367:Baculoviridae / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000096:biosynthesis / Q000276:immunology; D018604:Epitope Mapping; D018985:Epitopes, B-Lymphocyte / Q000032:analysis; D018984:Epitopes, T-Lymphocyte / Q000032:analysis; D005110:Extracellular Space / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood / Q000494:pharmacology; D007273:Injections, Intramuscular; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D019713:Receptors, CCR5 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000502:physiology; D018411:Spodoptera / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014162:Transfection; D015854:Up-Regulation / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D019742:Chemokines, CC; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D010446:Peptide Fragments; D019713:Receptors, CCR5