Amino-terminal alteration of the HLA-A*0201-restricted human immunodeficiency virus pol peptide increases complex stability and in vitro immunogenicity

Rebecca R. Pogue, Joseph Eron, Jeffrey A. Frelinger, Masanori Matsui

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Initial studies suggested that major histocompatibility complex class I- restricted viral epitopes could he 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 I 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, I1V 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.

Original languageEnglish (US)
Pages (from-to)8166-8170
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number18
StatePublished - Aug 29 1995


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