Modulation of gp130 Cytokine Receptor Family by Herpes Simplex Virus 1 as a Strategy for Immune Evasion?

Abstract

HSV-1 is a neurotropic human pathogen that establishes lifelong latency in sensory neurons. Periodic reactivation causes mucocutaneous lesions and, in some cases, severe corneal and neurological disease. While HSV-1 utilizes numerous viral proteins to extensively reprogram host signaling pathways and evade antiviral responses, how it alters host cytokine receptor networks remains poorly understood. Here, we demonstrate that HSV-1 infection selectively downmodulates multiple members of the gp130 (glycoprotein 130) cytokine receptor family, including gp130, Oncostatin M receptor {beta} (OSMR-{beta}), and leukemia inhibitory factor receptor (LIFR), while sparing IL-6Ra and CNTFRa (Ciliary Neurotrophic Factor Receptor). Because gp130 is the central signaling component of the IL-6 cytokine family and mediates JAK/STAT3 activation, its elimination likely represents a viral strategy to suppress inflammatory and antiviral signaling. Consistent with this, HSV-1 does not induce IL-6 mRNA expression in productively infected cells, suggesting coordinated inhibition of both cytokine production and receptor availability. Mechanistically, we found that the viral RNase VHS is at least partially responsible for gp130 family receptor downmodulation, likely in combination with virus-induced endocytosis/degradation pathways. Functionally, activation of gp130 signaling significantly impairs HSV-1 infection, demonstrating that suppression of antiviral cytokine responses is critical for virus replication. Finally, we determined that CNTF causes reactivation of latent HSV-1 using the LUHMES in vitro latency model, illustrating CNTFRa signaling contribution to latency and reactivation. A similar effect has been reported for IL-6. Together, these findings reveal a previously unrecognized immune evasion mechanism by which HSV-1 remodels gp130 cytokine signaling to promote infection.