title: Conversion of an immunogenic human immunodeficiency virus (HIV) envelope synthetic peptide to a tolerogen in chimpanzees by the fusogenic domain of HIV gp41 envelope protein.
abstract: The fusogenic (F) domain of human immunodeficiency virus (HIV) gp41 envelope (env) protein has sequence similarities to many virus and mediates the fusion of HIV-infected cells. During a survey of the immunogenicity of HIV env peptides in chimpanzees, we have observed that HIV peptide immunogenicity was dramatically altered by the NH2-terminal synthesis of the gp41 F domain to an otherwise immunogenic peptide. We compared two hybrid peptide types comprised of T helper (Th) and B cell epitopes of HIV gp120 env protein for their immunogenicity in chimpanzees. The Th-B epitope hybrid peptides contained the HIV gp120 Th cell determinant, T1 (amino acids [aa] 428-440)-synthesized NH2 terminal to gp120 V3 loop peptides, which contain B cell epitopes that induce anti-HIV-neutralizing antibodies (SP10IIIB [aa 303-321] and SP10IIIB [A] [aa 303-327]). The F-Th-B peptide contained the HIV gp41 F domain of HIVIIIB gp41 (aa 519-530)-synthesized NH2 terminal to the Th-B peptide. Whereas Th-B peptides were potent immunogens for chimpanzee antibody and T cell-proliferative responses, the F-Th-B peptide induced lower anti-HIV gp120 T and B cell responses. Moreover, immunization of chimpanzees with F-Th-B peptide but not Th-B peptides induced a significant decrease in peripheral blood T lymphocytes (mean decrease during immunization, 52%; p < 0.02). Chimpanzees previously immunized with F-Th-B peptide did not respond well to immunization with Th-B peptide with T or B cell responses to HIV peptides, demonstrating that the F-Th-B peptide induced immune hyporesponsiveness to Th and B HIV gp120 env determinants. These observations raise the hypothesis that the HIV gp41 env F domain may be a biologically active immunoregulatory peptide in vivo, and by an as yet uncharacterized mechanism, promotes primate immune system hyporesponsiveness to otherwise immunogenic peptides.
authors.affiliation: Department of Medicine, Duke Center for AIDS Research, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: B F
authors.initials: BF
authors.lastname: Haynes
authors.forename: L O
authors.initials: LO
authors.lastname: Arthur
authors.forename: P
authors.initials: P
authors.lastname: Frost
authors.forename: T J
authors.initials: TJ
authors.lastname: Matthews
authors.forename: A J
authors.initials: AJ
authors.lastname: Langlois
authors.forename: T J
authors.initials: TJ
authors.lastname: Palker
authors.forename: M K
authors.initials: MK
authors.lastname: Hart
authors.forename: R M
authors.initials: RM
authors.lastname: Scearce
authors.forename: D M
authors.initials: DM
authors.lastname: Jones
authors.forename: C
authors.initials: C
authors.lastname: McDanal
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis / Q000276:immunology; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D006041:Goats; D015699:HIV Envelope Protein gp120 / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009930:Organic Chemicals; D002679:Pan troglodytes; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000914:Antibodies, Viral; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D007166:Immunosuppressive Agents; D009930:Organic Chemicals; C029248:Tolerogen