Amino-terminal alteration of the HLA-A0201-restricted human immunodeficiency virus pol peptide increases complex stability and in vitro immunogenicity

• Published in: Proceedings of the National Academy of Sciences - PNAS 1995-08, Vol.92 (18), p.8166-8170
• Main Authors: Pogue, R R, Eron, J, Frelinger, J A, Matsui, M
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Amino Acid Sequence; Base Sequence; Cell Line; DNA Primers; Epitopes - genetics; Epitopes - immunology; Epitopes - metabolism; Gene Products, pol - genetics; Gene Products, pol - immunology; HIV-1 - immunology; HLA-A Antigens - immunology; human immunodeficiency virus 1; Humans; Molecular Sequence Data; T-Lymphocytes, Cytotoxic - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.18.8166

Initial studies suggested that major histocompatibility complex class I-restricted viral epitopes could be predicted by the presence of particular residues termed anchors. However, recent studies showed that nonanchor positions of the epitopes are also significant for class I binding and recognition by cytotoxic T lymphocytes (CTLs). We investigated if changing nonanchor amino acids could increase class I affinity, complex stability, and T-cell recognition of a natural viral epitope. This concept was tested by using the HLA-A 0201-restricted human immunodeficiency virus type 1 epitope from reverse transcriptase (pol). Position 1 (P1) amino acid substitutions were emphasized because P1 alterations may not alter the T-cell receptor interaction. The peptide with the P1 substitution of tyrosine for isoleucine (I1Y) showed a binding affinity for HLA-A 0201 similar to that of the wild-type pol peptide in a cell lysate assembly assay. Surprisingly, I1Y significantly increased the HLA-A 0201-peptide complex stability at the cell surface. I1Y sensitized HLA-A 0201-expressing target cells for wild-type pol-specific CTL lysis as well as wild-type pol. Peripheral blood lymphocytes from three HLA-A2 HIV-seropositive individuals were stimulated in vitro with I1Y and wild-type pol. I1Y stimulated a higher wild-type pol-specific CTL response than wild-type pol in all three donors. Thus, I1Y may be an "improved" epitope for use as a CTL-based human immunodeficiency virus vaccine component. The design of improved epitopes has important ramifications for prophylaxis and therapeutic vaccine development.