title: Selective side-chain modification of cysteine and arginine residues blocks pathogenic activity of HIV-1-Tat functional peptides.
abstract: Extracellular Tat protein of HIV-1 activates virus replication in HIV-infected cells and induces a variety of host factors in the uninfected cells, some of which play a critical role in the progression of HIV infection. The cysteine-rich and arginine-rich basic domains represent key components of the HIV-Tat protein for pathogenic effects of the full-length Tat protein and, therefore, could be ideal candidates for the development of a therapeutic AIDS vaccine. The present study describes selective modifications of the side-chain functional groups of cysteine and arginine amino acids of these HIV-Tat peptides to minimize the pathogenic effects of these peptides while maintaining natural peptide linkages. Modification of cysteine by introducing either a methyl or t-butyl group in the free sulfhydryl group and replacing the guanidine group with a urea linkage in the side chain of arginine in the cysteine-rich and arginine-rich Tat peptide sequences completely blocked the ability of these peptides to induce HIV replication, chemokine receptor CCR-5 expression, and NF-kappaB activity in monocytes. Such modifications also inhibited angiogenesis and migration of Kaposi's sarcoma cells normally induced by Tat peptides. Such chemical modifications of the cysteine-rich and arginine-rich peptides did not affect their reactivity with antibodies against the full-length Tat protein. With an estimated 40 million HIV-positive individuals worldwide and approximately 4 million new infections emerging every year, a synthetic subunit HIV-Tat vaccine comprised of functionally inactive Tat domains could provide a safe, effective, and economical therapeutic vaccine to reduce the progression of HIV disease.
authors.affiliation: Immunopathogenesis Section, Laboratory of Molecular Virology, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike (HFM-315), Rockville, MD 20852-1448, USA.
authors.forename: Krishnakumar
authors.initials: K
authors.lastname: Devadas
authors.forename: Robert A
authors.initials: RA
authors.lastname: Boykins
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Hardegen
authors.forename: Deborah
authors.initials: D
authors.lastname: Philp
authors.forename: Hynda K
authors.initials: HK
authors.lastname: Kleinman
authors.forename: Etin-Osa
authors.initials: EO
authors.lastname: Osa
authors.forename: Jiun
authors.initials: J
authors.lastname: Wang
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Clouse
authors.forename: Larry M
authors.initials: LM
authors.lastname: Wahl
authors.forename: Indira K
authors.initials: IK
authors.lastname: Hewlett
authors.forename: Jay
authors.initials: J
authors.lastname: Rappaport
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Yamada
authors.forename: Subhash
authors.initials: S
authors.lastname: Dhawan
mesh_terms: D001120:Arginine / Q000737:chemistry*; D002460:Cell Line; D045744:Cell Line, Tumor; D003545:Cysteine / Q000737:chemistry*; D004261:DNA Replication; D004789:Enzyme Activation; D015696:Gene Products, tat / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D015394:Molecular Structure; D016328:NF-kappa B; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D015696:Gene Products, tat; D016328:NF-kappa B; D010446:Peptide Fragments; D019713:Receptors, CCR5; D011994:Recombinant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C422951:tat peptide (48-60), Human immunodeficiency virus 1; D001120:Arginine; D003545:Cysteine