Role of IFN-α/β signaling in the prevention of genital herpes virus type 2 infection

Abstract

Genital herpes, caused by herpes simplex virus type 2 (HSV-2), is the most common genital ulcer disease worldwide. HSV-2 infection causes a variety of symptoms, ranging from subclinical/silent infection to severe and recurrent episodes of genital blisters and ulcers, and the virus can also in rare cases cause meningitis. In primary infection, the virus sequentially enters and replicates in epithelial cells followed by local sensory neurons. In the latter, a life-long infection is established via the induction of viral latency or dormancy. Latent virus is however continuously reactivated, also in those with a silent infection, which results in a low-grade viral replication and shedding into the vaginal lumen. This reactivation can in many individuals be amplified following e.g. stress, hormonal variations or immune suppression, which results in recurrent genital disease.

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

“…Thus, poly(I:C) might have most potential as a topical strategy that could be applied immediately within 24 h after exposure to curb local spread. In addition, the ability of TLR3 ligation to limit herpes simplex virus infection (4,28,33,63,76) would also help to control the spread of HIV (11).…”

Loss of the Type I Interferon Pathway Increases Vulnerability of Mice to Genital Herpes Simplex Virus 2 Infection

“…Synthetic CpG-containing oligonucleotides that activate TLRs have been experimentally used to induce an antiviral state following vaginal instillation (5,21,52). Central to the antiviral effect of TLR ligands is the production of IFN-␣ by plasmacytoid dendritic cells (pDCs) (34,55). The importance of type I IFNs in resistance to HSV-2 infection is also suggested by the fact that topical application of IFN-␣1-expressing plasmids to the vaginal epithelium increases the resistance of mice to HSV-2 challenge and spread (26).…”

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

“…pDCs deficient in TLR9 are unable to produce IFN−α upon HSV-2 stimulation [72,73] and, in vivo, TLR9-/-mice infected with HSV-2 have no detectable circulating IFN−α resulting in the rapid pathology and reduced survival of these mice [74,75]. Consistent with the importance of type I IFNs in the anti-HSV response, IFNAR1-/-mice have increased susceptibility to HSV-2 infection, with elevated viral replication [76]. Similarly, STAT1-/-mice demonstrate increased HSV-1 replication in the cornea [77].…”

“…Mouse models have demonstrated that TLR agonists can provide protective immunity in vaccination against HSV infection [95,96] through induction of IFN signaling pathways [76]. With vaginal administration of the TLR9 ligand, CpG oligodeoxynucleotide, mice were protected from a HSV-2 vaginal infection [75,97]; however, the mechanism for protection was unclear.…”

“…With vaginal administration of the TLR9 ligand, CpG oligodeoxynucleotide, mice were protected from a HSV-2 vaginal infection [75,97]; however, the mechanism for protection was unclear. Although not discussed here, type II IFN responses are crucial for the development of Th1 immunity to HSV-2 infections [76]. Elucidating the virus-specific pathways that mediate the anti-HSV mechanisms of IFN, as well as the induction of a specific IFN gene signature to define an appropriate antiviral response in HSV infection, may facilitate the design of tailored therapeutics of prognostic potential.…”