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Journal of Virology, August 2007, p. 8685-8691, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00415-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Lambda Interferon (IFN-) in Serum Is Decreased in Hantavirus-Infected Patients, and In Vitro-Established Infection Is Insensitive to Treatment with All IFNs and Inhibits IFN--Induced Nitric Oxide Production

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, S-171 77 Stockholm, Sweden,¹ Centre for Microbiological Preparedness, Swedish Institute for Infectious Disease Control, S-171 82 Solna, Sweden,² Division of Infectious Diseases, Department of Clinical Microbiology, Umeå University, S-901 85 Umeå, Sweden³

Received 27 February 2007/ Accepted 16 May 2007

Hantaviruses, causing hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), are known to be sensitive to nitric oxide (NO) and to pretreatment with type I and II interferons (alpha interferon [IFN-]/IFN-ß and IFN-, respectively). Elevated serum levels of NO and IFN- have been observed in HFRS patients, but little is known regarding the systemic levels of other IFNs and the possible effects of hantaviruses on innate antiviral immune responses. In Puumala virus-infected HFRS patients (n = 18), we report that the levels of IFN- and IFN-ß are similar, whereas the level of IFN- (type III IFN) is significantly decreased, during acute (day of hospitalization) compared to the convalescent phase. The possible antiviral effects of IFN- on the prototypic hantavirus Hantaan virus (HTNV) replication was then investigated. Pretreatment of A549 cells with IFN- alone inhibited HTNV replication, and IFN- combined with IFN- induced additive antiviral effects. We then studied the effect of postinfection treatment with IFNs. Interestingly, an already-established HTNV infection was insensitive to subsequent IFN-, -ß, -, and - stimulation, and HTNV-infected cells produced less NO compared to noninfected cells when stimulated with IFN- and IL-1ß. Furthermore, less phosphorylated STAT1 after IFN treatment was observed in the nuclei of infected cells than in those of noninfected cells. The results suggest that hantavirus can interfere with the activation of antiviral innate immune responses in patients and inhibit the antiviral effects of all IFNs. We believe that future studies addressing the mechanisms by which hantaviruses interfere with the activation and shaping of immune responses may bring more knowledge regarding HFRS and HCPS pathogenesis.

Published ahead of print on 23 May 2007.