Beta interferon plus gamma interferon efficiently reduces acyclovir-resistant herpes simplex virus infection in mice in a T-cell-independent manner

Abstract

Acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) causes severe diseases in immunocompromised patients, so identification of new therapies is needed. Interferons (IFNs) are used to treat several other viral infections in the clinic, and IFN-b and IFN-c are known to cooperatively reduce wild-type HSV-1 replication in the corneas of immunocompetent mice. Because IFN-c has been shown to exert an antiviral effect mostly through T cells, whether combined IFN treatment can still inhibit ACV-resistant HSV-1 replication, especially in immunocompromised hosts, is unknown. The present study evaluated the efficacy of combined IFN treatment on ACV-resistant HSV-1 mutants. In vitro results showed that IFN-b acted synergistically with IFN-c to inhibit HSV-1 replication in both human and mouse cell lines. Some ACV-resistant mutants were actually hypersensitive to combined IFN treatment. In vivo results showed that topical treatment with a low dose of IFN-b plus IFN-c (200 U each) on mouse corneas efficiently reduced the viral loads by up to 4, 4 and 3 logs, respectively, in the eyes, trigeminal ganglia and brainstems of wild-type and also immunocompromised nude mice infected or co-infected with ACV-resistant HSV-1 in a manner independent of T cells. A highly efficient reduction in HSV acute replication by combined IFN treatment led to a dramatic decrease in subsequent virus reactivation from neural tissues, trigeminal ganglia, brainstems and spinal cords of latently infected mice. Thus, a combination of IFN-b and IFN-c could be a potential treatment for ACV-resistant HSV-1 in immunocompromised patients.

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

“…The transient induction of host innate responses may explain the reduced viral titer detected during acute infection compared to that detected during persistent infection. Our previous in vitro study (37) showing that tkLTRZ1 is susceptible to treatments with type I interferons (interferon alpha or beta) and especially the combination of type I (interferon beta) and type II (interferon gamma) interferons supports this possibility.…”

Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts

“…Fortunately, the combined use of IFN‐β with IFN‐γ was shown to be highly effective in reducing mutant virus replication in cell cultures and in vivo in mice [Huang et al . (119)]. The researchers suggested that for therapy, frequent IFN treatment or IFN together with anti‐HSV drugs, such as foscarnet, which target viral DNA polymerase, could be used.…”

The yin and yang of viruses and interferons

“…However, IFN-g alone may have limited efficacy in immunocompromised HSV-1-infected individuals lacking a robust adaptive immune response. Recent studies have shown that when immunocompromised nude mice are infected with a DAA (acyclovir)-resistant HSV-1 variant and treated with IFN-b in combination with IFN-g, viral infection is reduced [65]. These preliminary data are in further support of the broadspectrum antiviral activities of IFNs-a/b.…”

“…For immunocompromised individuals infected with HSV-1, viral pathogenesis can lead to serious life-threatening disease; more so in the context of emergent drug-resistant HSV-1 strains [65][66][67]. Different DAAs have been used to control HSV-1 infection, including acyclovir, penciclovir and foscarnet, resulting in the emergence of DAA-resistant HSV-1 strains [65][66][67]. IFN-g is able to exert antiviral activity by stimulating a T cell response.…”