Administration of different antigenic forms of altered peptide ligands derived from HIV-1 RTase influences their effects on T helper cell activation.
Genetic hypervariability of viruses such as HIV-1 facilitates appearance of escape mutants for immune response. HIV-1 isolates display variant epitopes, which may fail to stimulate T-lymphocyte responses or act as natural T-cell receptor antagonists, contributing to viral persistence. We evaluated the effect on epitope specific T-cell reactions of different amino acid substitutions in a residue of the 248-262 sequence of HIV-1 reverse transcriptase (peptide 23), showing variability in different viral isolates. Responses against such a determinant have been detected in long-term nonprogressive patients. The modified antigenic determinant was administered either as synthetic peptide or as recombinant protein. Our results show that certain amino acid substitutions abolished peptide binding to major histocompatibility complex (MHC); other modifications, although not affecting the formation of the MHC/peptide complex, either abrogated T-cell proliferation or exhibited an antagonistic effect. The results suggest that residue 11 of peptide 23 exhibits a double function; its alteration affects both the peptide affinity for the MHC and the MHC/peptide complex affinity for the T-cell receptor. Furthermore, we demonstrated that synthetic ligands and recombinant proteins may produce distinct functional effects, providing evidence that synthetic peptides, compared with corresponding epitopes generated by intracellular processing of recombinant proteins, may bind to the MHC groove in a different conformation.
Moschella
Federica
F
Division of Medical Oncology, Department of Medicine of the College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Ombra
Maria Neve
MN
Del Pozzo
Giovanna
G
Guardiola
John
J
D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D015488:HIV Antigens / Q000276:immunology*; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000939:Epitopes; D015488:HIV Antigens; D010446:Peptide Fragments; D054303:HIV Reverse Transcriptase