Nitric oxide and peroxynitrite have different antiviral effects against hantavirus replication and free mature virions.
Reactive nitrogen intermediates (RNI), like nitric oxide (NO) and peroxynitrite, have antiviral effects against certain viruses. Hantaviruses, like other members of the Bunyaviridae family, have previously not been shown to be sensitive to RNI. In this study, we compared the effects of NO and peroxynitrite on hantavirus replication and free mature virions in vitro, and of inducible nitric oxide synthase (iNOS) in hantavirus-infected suckling mice. The NO-generating compound S-nitroso-N-acetylpenicillamine (SNAP), as well as cytokine-induced NO, strongly inhibited hantavirus replication in Vero E6 cells, while pretreatment of free virions with SNAP only had a limited effect on their viability. In contrast, 3-morpholinosydnonimine hydrochloride (SIN-1), a peroxynitrite donor, inhibited virus replication only to a very low extent in vitro, but pretreatment of virus with SIN-1 led to a considerably lowered viability of the virions. Infections of various human cell types per se did not induce NO production. The viral titers in iNOS(-/-) mice were higher compared to the controls, suggesting that NO inhibits hantavirus replication in vivo. In conclusion, we show that NO has strong antiviral effects on hantavirus replication, and peryoxynitrite on mature free virions, suggesting that different RNI can have different effects on various parts of the replication cycle for the same virus.
Klingström
Jonas
J
Swedish Institute for Infectious Disease Control, Solna, Sweden. Jonas.Klingstrom@smi.ki.se
Akerström
Sara
S
Hardestam
Jonas
J
Stoltz
Malin
M
Simon
Melinda
M
Falk
Kerstin I
KI
Mirazimi
Ali
A
Rottenberg
Martin
M
Lundkvist
Ake
A
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000821:virology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006476:Orthohantavirus / Q000187:drug effects* / Q000502:physiology; D018778:Hantavirus Infections / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014709:Vero Cells; D014771:Virion / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D020030:Nitric Oxide Donors; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D008981:Molsidomine; D052247:Nitric Oxide Synthase Type II