Multiple antiviral activities of cyanovirin-N: blocking of human immunodeficiency virus type 1 gp120 interaction with CD4 and coreceptor and inhibition of diverse enveloped viruses.
Cyanovirin-N (CV-N) is a cyanobacterial protein with potent neutralizing activity against human immunodeficiency virus (HIV). CV-N has been shown to bind HIV type 1 (HIV-1) gp120 with high affinity; moreover, it blocks the envelope glycoprotein-mediated membrane fusion reaction associated with HIV-1 entry. However, the inhibitory mechanism(s) remains unclear. In this study, we show that CV-N blocked binding of gp120 to cell-associated CD4. Consistent with this, pretreatment of gp120 with CV-N inhibited soluble CD4 (sCD4)-dependent binding of gp120 to cell-associated CCR5. To investigate possible effects of CV-N at post-CD4 binding steps, we used an assay that measures sCD4 activation of the HIV-1 envelope glycoprotein for fusion with CCR5-expressing cells. CV-N displayed equivalently potent inhibitory effects when added before or after sCD4 activation, suggesting that CV-N also has blocking action at the level of gp120 interaction with coreceptor. This effect was shown not to be due to CV-N-induced coreceptor down-modulation after the CD4 binding step. The multiple activities against the HIV-1 envelope glycoprotein prompted us to examine other enveloped viruses. CV-N potently blocked infection by feline immunodeficiency virus, which utilizes the chemokine receptor CXCR4 as an entry receptor but is CD4 independent. CV-N also inhibited fusion and/or infection by human herpesvirus 6 and measles virus but not by vaccinia virus. Thus, CV-N has broad-spectrum antiviral activity, both for multiple steps in the HIV entry mechanism and for diverse enveloped viruses. This broad specificity has implications for potential clinical utility of CV-N.
Dey
B
B
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0445, USA.
Lerner
D L
DL
Lusso
P
P
Boyd
M R
MR
Elder
J H
JH
Berger
E A
EA
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001426:Bacterial Proteins; D015704:CD4 Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology*; D002415:Cats; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000187:drug effects / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects*; D015654:Herpesvirus 6, Human / Q000187:drug effects; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000187:drug effects; D008459:Measles virus / Q000187:drug effects; D008561:Membrane Fusion / Q000187:drug effects; D051379:Mice; D019713:Receptors, CCR5 / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism*
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D001426:Bacterial Proteins; D015704:CD4 Antigens; D002352:Carrier Proteins; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D014759:Viral Envelope Proteins; C107733:cyanovirin N