Effects of type I interferons on Friend retrovirus infection

Abstract

The type I interferon (IFN) response plays an important role in the control of many viral infections. However, since there is no rodent animal model for human immunodeficiency virus, the antiviral effect of IFN-alpha and IFN-beta in retroviral infections is not well characterized. In the current study we have used the Friend virus (FV) model to determine the activity of type I interferons against a murine retrovirus. After FV infection of mice, IFN-alpha and IFN-beta could be measured between 12 and 48 h in the serum. The important role of type I IFN in the early immune defense against FV became evident when mice deficient in IFN type I receptor (IFNAR(-/-)) or IFN-beta (IFN-beta(-/-)) were infected. The levels of FV infection in plasma and in spleen were higher in both strains of knockout mice than in C57BL/6 wild-type mice. This difference was induced by an antiviral effect of IFN-alpha and IFN-beta and was most likely mediated by antiviral enzymes as well as by an effect of these IFNs on T-cell responses. Interestingly, the lack of IFNAR and IFN-beta enhanced viral loads during acute and chronic FV infection. Exogenous IFN-alpha could be used therapeutically to reduce FV replication during acute but not chronic infection. These findings indicate that type I IFN plays an important role in the immediate antiviral defense against Friend retrovirus infection.

FIG. 1.

Antiviral effect of IFN-α and IFN-β in vitro. Mus dunnis cells were treated in vitro for 24 h with increasing concentrations of IFN-α or IFN-β (1 to 1,000 U/ml). Inhibition of viral replication was determined 4 days after infection of the cells with 50 FFU of F-MuLV virus. Each IFN-α/β concentration was titrated in duplicate. Similar results were obtained in two independent experiments.

FIG. 2.

Kinetics of IFN-α and IFN-β after FV infection. Mice were infected with FV, and blood was collected at the indicated time points postinfection. IFN-α and IFN-β levels were determined in the plasma by ELISA. (A) Kinetics of IFN-α production was determined for two mouse strains susceptible to FV-induced leukemia and two resistant mouse strains. (B) Kinetics of IFN-α production was compared with that of IFN-β production in susceptible (B10.A × A.BY)F₁ mice. Four animals per group were analyzed. Standard deviations are indicated by a bar. was documented by spleen weights (A), and viral loads were measured in the spleen (B) and in the blood (C). The mean value for each group is indicated by a bar. Differences between the control group and the two groups of IFN-α-treated mice were analyzed by using Dunnett's multiple-comparison correction test. Statistically significant differences between the groups are indicated.

FIG. 3.

Acute FV infection in mice deficient for IFN-β or IFNAR. C57BL/6 wild-type or knockout mice that lack IFN-β or IFN type I receptor (IFNAR) were infected with FV. Viral loads were measured at 11 days after infection in the spleen (A) and in the blood (B). The results for the knockout mice were compared with those obtained for wild-type mice. The mean value for each group is indicated by a bar. Differences between the group of infected wild-type mice and the groups of knockout mice were analyzed by using Dunnett's multiple-comparison correction test for comparing a control group to several experimental groups. Statistically significant differences between the groups are indicated.

FIG. 4.

IFN-α production after FV infection of mice deficient for IFN-β or IFNAR. Twenty-four hours postinfection, levels of IFN-α were determined by ELISA in plasma samples collected from the indicated knockout and control mice. Four animals per group were analyzed. Standard deviations are indicated by a bar.

FIG. 5.

Effect of IFN-α therapy on acute FV infection. Mice were given recombinant IFN-α A/D or (as a control) PBS on days −1 to +3 (treatment pre- and postinfection) or on day +3 and +4 (treatment postinfection) after infection with FV. Eleven days postinfection, disease progression and viral loads were analyzed. Virus-induced disease

FIG. 6.

B-, NK-, and T-cell responses in mice deficient in IFN-β or IFNAR. C57BL/6 wild-type and knockout mice that lack IFN-β or IFNAR were infected with FV. Eleven days postinfection, live, nucleated spleen cells were stained for CD19 (A), NK1.1/DX5 (B), CD4 (C), and CD8 (D). Dead cells were excluded by DAAD staining. Percentages from total splenocytes are shown. The mean value for each group is indicated by a bar. Differences between the group of infected wild-type mice and the groups of knockout mice were analyzed by using Dunnett's multiple-comparison correction test. Statistically significant differences between the groups are indicated.

FIG. 7.

Persistent FV infection in mice deficient in IFN-β or IFNAR. C57BL/6 wild-type or knockout mice that lack IFN-β or IFNAR were infected with FV. Viral loads were measured at 8 weeks after infection in the spleen. The results for knockout mice were compared with those for wild-type mice. The mean value for each group is indicated by a bar. Differences between the group of infected wild-type mice and the groups of knockout mice were analyzed by using Dunnett's multiple-comparison correction test. Statistically significant differences between the groups are given.