Host-cell Determinants of Interferon Control During Herpes Simplex Virus Infection

Abstract

Herpes simplex virus (HSV) infects a majority of the world’s population and can alternate between an active, lytic infection in the epithelia and a life-long latent infection in neurons. For successful replication and transmission to occur, HSV-1 must both counteract host-cell defenses and co-opt necessary components of the host-cell machinery. How host defenses silence incoming viral DNA and how herpesvirus-host interactions enable virus evasion of these cellular antiviral responses remains to be fully understood. In the first part of this dissertation, I identified an important role for the cellular restriction factor IFI16 not only as a component of the intrinsic cellular defense against HSV but also as one component of the host innate interferon (IFN) response to herpesvirus infection. IFI16 contributed to IFN-mediated restriction of wild-type HSV, and I found this restriction to be based on the stabilization of virus-associated heterochromatin. This research revealed that, during an active innate immune IFN response, herpesvirus gene transcription can be restricted in the host cell via IFI16-mediated epigenetic silencing of incoming viral DNA. In the second part of my dissertation work, I found that the cellular transcription factor Sp1 provides a critical back-up mechanism for the maintenance of HSV transcription and replication under adverse conditions. Sp1 enabled continued viral transcription and replication in the absence of key viral transactivators and enabled wild-type HSV to evade heightened antiviral defenses following IFN treatment. Interestingly, I observed reduced expression of Sp1-family transcription factors in fully differentiated sensory neurons compared to undifferentiated cells, suggesting that reduced Sp1 levels may contribute to the establishment of HSV latency. These findings highlight two distinct responses to IFN-mediated immune pressure during HSV infection of the host cell. Understanding the host-cell determinants of immune control versus virus escape will be key for developing therapeutic interventions at both the lytic and latent stages of herpesvirus infection.