Epitope-enhanced conserved HIV-1 peptide protects HLA-A2-transgenic mice against virus expressing HIV-1 antigen.
HIV epitopes may have developed to be poor immunogens. As a counterapproach HIV vaccine strategy, we used epitope enhancement of a conserved HIV reverse transcriptase (RT) epitope for induction of antiviral protection in HLA-A2-transgenic mice mediated by human HLA-A2-restricted CTLs. We designed two epitope-enhanced peptides based on affinity for HLA-A2, one substituted in anchor residues (RT-2L9V) and the other also with tyrosine at position 1 (RT-1Y2L9V), and examined the balance between HLA binding and T cell recognition. CTL lines and bulk cultures in two HLA-A2-transgenic mouse strains showed that RT-2L9V was more effective in inducing CTL reactive with wild-type Ag than RT-1Y2L9V, despite the higher affinity of the latter, because the 1Y substitution unexpectedly altered T cell recognition. Accordingly, RT-2L9V afforded the greatest protection in vivo against a surrogate virus expressing HIV-1 RT mediated by HLA-A2-restricted CTL in a mouse in which all CTL are restricted to only the human HLA molecule. Such antiviral protection has not been previously achieved with an HLA epitope-enhanced vaccine. These findings define a critical balance between MHC affinity and receptor cross-reactivity required for effective epitope enhancement and also demonstrate construction and efficacy of such a component of a new generation vaccine.
Okazaki
Takahiro
T
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 6B-12, Bethesda, MD 20892.
Pendleton
C David
CD
Lemonnier
François
F
Berzofsky
Jay A
JA
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000409:Alanine / Q000378:metabolism; D019943:Amino Acid Substitution / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation; D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis; D017124:Conserved Sequence / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D006183:H-2 Antigens / Q000235:genetics; D015488:HIV Antigens / Q000096:biosynthesis* / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D015497:HIV-1 / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000235:genetics*; D006801:Humans; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis; D007930:Leucine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D014443:Tyrosine / Q000378:metabolism; D014633:Valine / Q000378:metabolism
D000276:Adjuvants, Immunologic; D018946:Chemokine CCL5; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015488:HIV Antigens; D015789:HLA-A2 Antigen; D009842:Oligopeptides; D014443:Tyrosine; D007371:Interferon-gamma; D054303:HIV Reverse Transcriptase; D007930:Leucine; D014633:Valine; D000409:Alanine