Herpes Simplex Virus Evasion of Autophagy and Adaptive Immune Responses

Abstract

Purpose: : Autophagy is critical for innate and adaptive immunity to viruses. Autophagy, for example, is critical for innate degradation of intracellular pathogens, and for promoting MHC class II antigen presentation. Herpes simplex virus type 1 (HSV-1) infection induces autophagy but this response is antagonized by the HSV-1 neurovirulence gene product, ICP34.5 in part through its interaction with Beclin 1, a cellular protein essential for the induction of autophagy. The purpose of this study was to determine the role of ICP34.5-mediated blockade of autophagy in corneal infection and immune evasion.

Methods: : A recombinant viruses lacking the beclin-binding domain (BD) of ICP34.5 (ΔBD) and its marker-rescued virus (ΔBD^R) were tested for their pathogenesis in vivo using the mouse ocular model in wild type mice, and mice lacking the critical interferon-regulated antiviral factor IRF3 (IRF3^-/-), and lacking functional T and B cells (Rag1^-/-). In addition these viruses were tested for their abilities to stimulate T cell responses using a delayed-type hypersensitivity (DTH) assay following corneal infection with ΔBD or ΔBD^R.

Results: : ΔBD replicated in primary cell culture equiavlently to ΔBD^R, but in mice was cleared more rapidly than ΔBD^R from all tissues at late times following corneal infection. ΔBD also induced less ocular disease than ΔBD^R. Following intracerebral infection ΔBD was attenuated compared with ΔBD^R, and this neurovirulence was restored to ΔBD in Rag1-/, but not in IRF3-/- mice. ΔBD stimulated a significantly stronger DTH response than ΔBD^R. This strong response was ablated by depletion of CD4⁺, but not CD8⁺ T cells.

Conclusions: : The regulation of autophagy by HSV-1’s ICP34.5 gene product is mediated in part through its Beclin 1 interaction domain. This domain is dispensable for replication in vitro and for early replication in vivo. Its importance for replication late in infection suggested a role in countering adaptive immunity, confirmed by the increased CD4⁺ T cell responses to ΔBD compared to ΔBD^R. Together these data suggest a role for this beclin binding domain of ICP34.5 in precluding autophagy-mediated class II antigen presentation and thereby for enhancing the virulence and pathogenesis of HSV-1.

Keywords: herpes simplex virus • immunomodulation/immunoregulation