Detailed analysis of CD4+ Th responses to envelope and Gag proteins of simian immunodeficiency virus reveals an exclusion of broadly reactive Th epitopes from the glycosylated regions of envelope.
Ag-specific CD4(+) Th cells play a key role in the development, maturation, and maintenance of pathogen-specific humoral and cellular immune responses. To define the fine specificity of broadly reactive Th responses associated with mature immunity in a lentiviral system, we analyzed peptide-specific Th responses in eight macaques chronically infected with a reference live attenuated SIV at 12-14 mo postinoculation. All macaques had stable immunocompetent Th cells at the time of analysis, and a unique array of Th responses to 20-mer overlapping peptides from envelope (Env) and Gag was identified for each macaque, which were then used to define a set of 31 broadly reactive peptide epitopes. Only 5 of the 31 broadly reactive Th epitope peptides mapped to the surface (SU) domain of Env. Interestingly, these were all confined to two conserved nonglycosylated regions toward the carboxyl terminus of SU, suggesting a structural influence of glycosylation on development of Th responses. Gag and the Env transmembrane proteins contained the majority of broadly reactive peptide epitopes (12 and 14 peptides, respectively), which were uniformly distributed throughout their sequence. This study defines for the first time broadly reactive Th epitope peptides of SIV Env and Gag proteins that are associated with enduring broadly protective vaccine immunity to attenuated SIV, which may be used for the design and evaluation of experimental vaccines. Moreover, the data suggest that extensive glycosylation of SU may provide yet another immune escape mechanism developed by lentiviruses to restrict the breadth of Th repertoire to SU, a major immunologically exposed protein of the virus.
Sarkar
Surojit
S
Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Kalia
Vandana
V
Murphey-Corb
Michael
M
Montelaro
Ronald C
RC
D000375:Aging / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000937:Antigen-Antibody Reactions; D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D017124:Conserved Sequence; D018984:Epitopes, T-Lymphocyte / Q000032:analysis / Q000276:immunology* / Q000378:metabolism*; D005452:Fluoresceins / Q000032:analysis; D015686:Gene Products, env / Q000032:analysis / Q000276:immunology* / Q000378:metabolism*; D015683:Gene Products, gag / Q000032:analysis / Q000276:immunology* / Q000378:metabolism*; D006031:Glycosylation; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007111:Immunity, Cellular / Q000502:physiology; D019394:Ki-67 Antigen / Q000032:analysis; D008213:Lymphocyte Activation / Q000276:immunology; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000276:immunology; D008934:Mitogens / Q000276:immunology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000032:analysis / Q000276:immunology; D010449:Peptide Mapping; D017433:Protein Structure, Secondary; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000378:metabolism; D013388:Succinimides / Q000032:analysis; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D000956:Antigens, Viral; D015415:Biomarkers; D018984:Epitopes, T-Lymphocyte; D005452:Fluoresceins; D015686:Gene Products, env; D015683:Gene Products, gag; D000949:Histocompatibility Antigens Class II; D019394:Ki-67 Antigen; D008562:Membrane Glycoproteins; D008934:Mitogens; D010446:Peptide Fragments; D018449:SAIDS Vaccines; D013388:Succinimides; D014613:Vaccines, Attenuated