Differential inhibition of HIV-1 and SIV envelope-mediated cell fusion by C34 peptides derived from the C-terminal heptad repeat of gp41 from diverse strains of HIV-1, HIV-2, and SIV.
The spectrum of inhibition of human (HIV) and simian (SIV) immunodeficiency virus envelope (Env)-mediated cell fusion by C34, a 34 residue peptide corresponding to the C-heptad repeat of gp41 (residues 628-661 of HIV-1 Env), has been examined using a panel of five envelope glycoproteins, three from HIV-1 (LAV, SF162 and 89.6) and two from SIV (mac239 and mac316), and six C34 peptides derived from three strains of HIV-1 (LAV, N CM, and O CM), two strains of HIV-2 (EHO and ALI), and one strain of SIV (African Green Monkey, AGM). A quantitative vaccinia-based reporter gene cell fusion assay was employed. The inhibition data from the panel of 30 C34/envelope glycoprotein combinations, which can be fit to a simple activity relationship with IC(50) values spanning a range of over 4 orders of magnitude from 4 nM to 70 microM, permits one to rationalize both the potency and broadness of the inhibitory properties of the C34 peptides in terms of computed interaction free energies between the C34 peptides and the N-helical trimeric coiled-coil of gp41 and the helical propensities of the free C34 peptides. Of particular interest is the finding that the C34 peptide derived from the EHO strain of HIV-2 is a broad spectrum, highly potent inhibitor of Env-mediated cell fusion with IC(50) values spanning a very narrow range from only 4 to 25 nM over the entire panel of HIV-1 and SIV envelope glycoproteins tested. This result suggests that C34 from HIV-2 EHO may present a potentially useful therapeutic agent against diverse and/or resistant strains of HIV-1.
Gustchina
Elena
E
Laboratory of Chemical Physics, Building 5, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA.
Hummer
Gerhard
G
Bewley
Carole A
CA
Clore
G Marius
GM
D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002459:Cell Fusion; D002460:Cell Line; D002522:Chlorocebus aethiops; D002942:Circular Dichroism; D003198:Computer Simulation; D017930:Genes, Reporter; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry*; D015498:HIV-2 / Q000737:chemistry*; D008562:Membrane Glycoproteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D012191:Retroviridae Proteins / Q000737:chemistry*; D015302:Simian Immunodeficiency Virus / Q000737:chemistry*; D013816:Thermodynamics; D014616:Vaccinia virus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000502:physiology*
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D012191:Retroviridae Proteins; C082614:SIV envelope protein gp41; D014759:Viral Envelope Proteins; C407149:peptide C34