Mechanism of feline immunodeficiency virus envelope glycoprotein-mediated fusion.
Feline immunodeficiency virus (FIV) shares remarkable homology to primate lentiviruses, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). The process of lentiviral env glycoprotein-mediated fusion of membranes is essential for viral entry and syncytia formation. A detailed understanding of this phenomenon has helped identify new targets for antiviral drug development. Using a model based on syncytia formation between FIV env-expressing cells and a feline CD4+ T cell line we have studied the mechanism of FIV env-mediated fusion. Using this model we show that FIV env-mediated fusion mechanism and kinetics are similar to HIV env. Syncytia formation could be blocked by CXCR4 antagonist AMD3100, establishing the importance of this receptor in FIV gp120 binding. Interestingly, CXCR4 alone was not sufficient to allow fusion by a primary isolate of FIV, as env glycoprotein from FIV-NCSU(1) failed to induce syncytia in several feline cell lines expressing CXCR4. Syncytia formation could be inhibited at a post-CXCR4 binding step by synthetic peptide T1971, which inhibits interaction of heptad repeat regions of gp41 and formation of the hairpin structure. Finally, using site-directed mutagenesis, we also show that a conserved tryptophan-rich region in the membrane proximal ectodomain of gp41 is critical for fusion, possibly at steps post hairpin structure formation.
Garg
Himanshu
H
Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA.
Fuller
Frederick J
FJ
Tompkins
Wayne A F
WA
D000595:Amino Acid Sequence; D000818:Animals; D001596:Benzylamines; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D002415:Cats; D002460:Cell Line; D000080027:Cyclams; D015726:Giant Cells; D006571:Heterocyclic Compounds / Q000494:pharmacology; D016089:Immunodeficiency Virus, Feline / Q000302:isolation & purification / Q000502:physiology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology; D016415:Sequence Alignment; D014364:Tryptophan; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D010455:Peptides; D019718:Receptors, CXCR4; D014760:Viral Fusion Proteins; D014364:Tryptophan; C088327:plerixafor