Identification of a conserved universal Th epitope in HIV-1 reverse transcriptase that is processed and presented to HIV-specific CD4+ T cells by at least four unrelated HLA-DR molecules.

CD4+ Th cells play an important role in the induction and maintenance of specific T cell immunity. Indications for a protective role of CD4+ T cells against HIV-1 infection were found in subjects who were able to control HIV-1 viremia as well as in highly HIV-1-exposed, yet seronegative, individuals. This study describes the identification of an HIV-1-specific Th epitope that exhibits high affinity binding as well as high immunogenicity in the context of at least four different HLA-DR molecules that together cover 50-60% of the Caucasian, Oriental, and Negroid populations. This HIV-1 reverse transcriptase-derived peptide (RT171-190) is highly conserved among different HIV-1 isolates. Importantly, stimulation of PBL cultures from HIV-1 seronegative donors with this peptide resulted in Thl-type lymphocytes capable of efficient recognition of HIV-1-pulsed APCs. Taken together, these data indicate that peptide RT171-190 constitutes an attractive component of vaccines aiming at induction or enhancement of HIV-1-specific T cell immunity.

[1]  R Brookmeyer,et al.  Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. , 1997, Science.

[2]  A. Vitiello,et al.  Analysis of the HLA-restricted influenza-specific cytotoxic T lymphocyte response in transgenic mice carrying a chimeric human-mouse class I major histocompatibility complex , 1991, The Journal of experimental medicine.

[3]  S. Rowland-Jones,et al.  HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women , 1995, Nature Medicine.

[4]  de Fijter,et al.  Increased IL‐10 production by stimulated whole blood cultures in primary IgA nephropathy , 1998, Clinical and experimental immunology.

[5]  J. Berzofsky,et al.  Cellular immune factors associated with mother‐to-infant transmission of HIV , 1993, AIDS.

[6]  A. Trzeciak,et al.  A malaria T-cell epitope recognized in association with most mouse and human MHC class II molecules , 1988, Nature.

[7]  N. Nagelkerke,et al.  Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya , 1996, The Lancet.

[8]  J. Rothbard,et al.  Degenerate binding of immunogenic peptides to HLA-DR proteins on B cell surfaces. , 1990, International immunology.

[9]  E. Unanue,et al.  Identification of two distinct properties of class II major histocompatibility complex-associated peptides. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. H. van der Burg,et al.  Induction of a primary human cytotoxic T‐lymphocyte response against a novel conserved epitope in a functional sequence of HIV‐1 reverse transcriptase , 1995, AIDS.

[11]  R. Balderas,et al.  Human T helper cells specific for HIV reverse transcriptase: possible role in intrastructural help for HIV envelope‐specific antibodies , 1995, European journal of immunology.

[12]  B. Walker,et al.  HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in infected individuals. , 1988, Science.

[13]  J. Berzofsky,et al.  HIV-specific T-helper activity in seronegative health care workers exposed to contaminated blood. , 1994, JAMA.

[14]  A. Rudensky,et al.  Sequence analysis of peptides bound to MHC class II molecules , 1991, Nature.

[15]  R. Offringa,et al.  Immunization with human papillomavirus type 16 (HPV16) oncoprotein-loaded dendritic cells as well as protein in adjuvant induces MHC class I-restricted protection to HPV16-induced tumor cells. , 1998, Cancer research.

[16]  W. Heath,et al.  Induction of a CD8+ Cytotoxic T Lymphocyte Response by Cross-priming Requires Cognate CD4+ T Cell Help , 1997, The Journal of experimental medicine.

[17]  Rob J. De Boer,et al.  Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: A composite of redistribution and proliferation , 1998, Nature Medicine.

[18]  Stephen P. Schoenberger,et al.  T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions , 1998, Nature.

[19]  A. Lazzarin,et al.  Antigen-driven C–C Chemokine-mediated HIV-1 Suppression by CD4+ T Cells from Exposed Uninfected Individuals Expressing the Wild-type CCR-5 Allele , 1997, The Journal of experimental medicine.

[20]  J. Berzofsky,et al.  ENV-specific cytotoxic T lymphocyte responses in HIV seronegative health care workers occupationally exposed to HIV-contaminated body fluids. , 1995, The Journal of clinical investigation.

[21]  W. Kast,et al.  Protection against lethal Sendai virus infection by in vivo priming of virus-specific cytotoxic T lymphocytes with a free synthetic peptide. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Zinkernagel,et al.  Peptide-induced antiviral protection by cytotoxic T cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Clerici,et al.  HIV-specific mucosal and cellular immunity in HIV-seronegative partners of HIV-seropositive individuals , 1997, Nature Medicine.

[24]  J. Drijfhout,et al.  Clip binds to HLA class II using methionine-based, allele-dependent motifs as well as allele-independent supermotifs. , 1995, Molecular immunology.

[25]  J. Drijfhout,et al.  A sensitive fluorometric assay for quantitatively measuring specific peptide binding to HLA class I and class II molecules. , 1997, Journal of immunological methods.

[26]  T. Ottenhoff,et al.  The impact of DR3 microvariation on peptide binding: the combinations of specific DR beta residues critical to binding differ for different peptides. , 1996, Human immunology.

[27]  L. Moretta,et al.  Occurrence of human immunodeficiency virus type 1 (HIV-1)-specific cytolytic T cell activity in apparently uninfected children born to HIV-1-infected mothers. , 1994, The Journal of infectious diseases.

[28]  J. Berzofsky,et al.  Human immunodeficiency virus reverse transcriptase T helper epitopes identified in mice and humans: correlation with a cytotoxic T cell epitope. , 1991, The Journal of infectious diseases.

[29]  S. Goff,et al.  Structural requirements for bacterial expression of stable, enzymatically active fusion proteins containing the human immunodeficiency virus reverse transcriptase. , 1988, DNA.

[30]  M. Baur,et al.  Population Analysis on the Basis of Deduced Haplotypes from Random Families , 1984 .

[31]  Michel Klein,et al.  Changing Virus‐Host Interactions in the Course of HIV‐1 Infection , 1994, Immunological reviews.

[32]  H. Rammensee,et al.  Fine specificity of cytotoxic T lymphocytes primed in vivo either with virus or synthetic lipopeptide vaccine or primed in vitro with peptide , 1991, The Journal of experimental medicine.

[33]  J. Orange,et al.  Early Murine Cytomegalovirus (MCMV) Infection Induces Liver Natural Killer (NK) Cell Inflammation and Protection Through Macrophage Inflammatory Protein 1α (MIP-1α)–dependent Pathways , 1998, The Journal of experimental medicine.

[34]  J. Forman,et al.  Helper activity is required for the in vivo generation of cytotoxic T lymphocytes , 1982, The Journal of experimental medicine.

[35]  J. Berzofsky,et al.  An epitope in human immunodeficiency virus 1 reverse transcriptase recognized by both mouse and human cytotoxic T lymphocytes. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[36]  E. Rosenberg,et al.  Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. , 1997, Science.

[37]  C. Griscelli,et al.  Cytotoxic T lymphocyte responses in the peripheral blood of children born to human immunodeficiency virus‐1‐infected mothers , 1992, European journal of immunology.

[38]  J. Wakefield,et al.  In vitro enzymatic activity of human immunodeficiency virus type 1 reverse transcriptase mutants in the highly conserved YMDD amino acid motif correlates with the infectious potential of the proviral genome , 1992, Journal of virology.

[39]  J. L. Raina,et al.  Factors underlying spontaneous inactivation and susceptibility to neutralization of human immunodeficiency virus. , 1992, Virology.

[40]  J. Habeshaw,et al.  The naive repertoire of human T helper cells specific for gp120, the envelope glycoprotein of HIV. , 1991, Journal of immunology.

[41]  C. Melief,et al.  Recognition of peptides corresponding to the joining region of p210BCR-ABL protein by human T cells. , 1995, Leukemia.

[42]  C Oseroff,et al.  Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. , 1994, Immunity.

[43]  C. Melief,et al.  Specific T Helper Cell Requirement for Optimal Induction of Cytotoxic T Lymphocytes against Major Histocompatibility Complex Class II Negative Tumors , 1998, The Journal of experimental medicine.

[44]  S. Rowland-Jones,et al.  HIV-specific cytotoxic T-cell activity in an HIV-exposed but uninfected infant , 1993, The Lancet.

[45]  F. Studier,et al.  Use of T7 RNA polymerase to direct expression of cloned genes. , 1990, Methods in enzymology.

[46]  A. Ferraris,et al.  Human CD4+ T cells can discriminate the molecular and structural context of T epitopes of HIV gp120 and HIV p66. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.