Differential Expression of IFN-Gamma Stimulated Antiviral Genes in Human Herpes Simplex Virus Infection

Abstract

Herpes simplex virus type 2 (HSV-2) causes highly prevalent and recurrent ulcerative disease that affects millions of individuals worldwide. Clinical outcomes vary widely, ranging from asymptomatic, subclinical illness to severe, painful ulcerations. HSV-2 prevalence is further associated with an elevated risk of human immunodeficiency virus (HIV) acquisition, due to the recruitment of HIV-susceptible CD4+ T cells to sites of mucocutaneous infection. As HSV can establish latency in sensory ganglia and reactivate throughout an individual’s lifetime, a host's innate and adaptive immune system must continuously surveil and contain viral activity. Viral containment is primarily attributed to HSV-specific CD8+ T cells that persist at sites of prior infection, alongside the network of chemokines and cytokines that coordinate local antiviral immune responses. Within the herpes lesion microenvironment, interferon gamma (IFN-γ) plays a critical role in viral control by inducing the expression of interferon-stimulated genes (ISGs) in neighboring cells, most notably keratinocytes and fibroblasts, which produce antiviral proteins, microbicidal molecules, phagocytic receptors, and additional immune modulators that help establish an antiviral state. In this study, we investigated donor-dependent IFN–γ–induced gene expression in primary structural cells isolated from individuals with asymptomatic or severe HSV-2 disease. By assessing the transcriptional response of specific ISGs in keratinocytes and fibroblasts exposed to IFN-γ, we identified distinct patterns of gene expression based on both donor phenotype and cell type. Our findings suggest that variability in the magnitude and regulation of IFN-γ-responsive genes may underlie the heterogeneous clinical manifestations of HSV-2 infection. Understanding the mechanisms that govern effective immune control can help us identify determinants of disease severity and inform the development of targeted therapeutic strategies aimed at long-term containment and eradication of HSV-2.