Non-infectious VZV EVS as a novel modulator of HSV-1 neurovirulence - herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) are neurotropic alphaherpesviruses that establish lifelong…

The National Institute of Allergy and Infectious Diseases awarded The Regents of the University of Colorado, doing business as University of Colorado-Denver, $429,000 on June 9, 2026, for research investigating how extracellular vesicles released from varicella-zoster virus-infected neurons modulate herpes simplex virus type 1 neurovirulence.

The project tests the hypothesis that non-infectious extracellular vesicles derived from VZV-infected neurons suppress innate immune responses in peripheral barrier tissues such as the olfactory epithelium, thereby facilitating greater HSV-1 replication, spread, and neuroinvasion. The research encompasses two primary aims. Aim 1A will determine how VZV-derived extracellular vesicles alter mucosal and olfactory immune responses to increase susceptibility to primary HSV-1 infection and identify mechanisms by which packaged VZV viral proteins (IE62) affect co-infection with HSV-1 in vitro. Aim 2A will evaluate whether VZV extracellular vesicle exposure is sufficient to induce HSV-1 reactivation from latency in vivo. Aim 2B will test whether intranasal interferon-beta supplementation can restore innate immune tone and suppress VZV extracellular vesicle-mediated HSV-1 reactivation. The award is a Project Grant under the Allergy and Infectious Diseases Research program (CFDA 93.855). Performance will occur at the recipient's Aurora, Colorado location through May 31, 2028.

Non-infectious VZV EVS as a novel modulator of HSV-1 neurovirulence - herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) are neurotropic alphaherpesviruses that establish lifelong latency in sensory ganglia and are capable of periodic reactivation. While each virus has been independently associated with neurological disease, CO-infection and CO-reactivation in human trigeminal ganglia (TG) are common and may exacerbate neurological and neurodegenerative outcomes. However, the mechanisms by which latent or subclinical activity of one virus may influence the pathogenic potential of the other remain poorly defined. Emerging evidence suggests that extracellular vesicles (EVS) released from VZV- infected neurons contain host and viral cargo that can modulate immune responses in neighboring cells. This project tests the central hypothesis that non-infectious EVS from VZV-infected neurons suppress innate immune responses in peripheral barrier tissues, such as the olfactory epithelium, thereby facilitating greater HSV-1 replication, spread, and neurovirulence. This immune suppression may accelerate HSV-1 neuroinvasion and increase the risk of CNS-related complications. Furthermore, we hypothesize that restoring interferon signaling, specifically through recombinant IFN-β treatment, will mitigate VZV EV- induced HSV-1 reactivation and preserve latency. In aim 1A, we will determine how VZV-derived EVS alter mucosal and olfactory immune responses to increase susceptibility to primary HSV-1 infection. We further identify novel mechanisms of packaged VZV viral proteins (IE62) and their effects with CO-infection of HSV-1 in vitro. In aim 2A, we will evaluate whether VZV EV exposure is sufficient to induce HSV-1 reactivation from latency in vivo. In aim 2B, we will test whether intranasal interferon-beta (IFN-β) supplementation can restore innate immune tone and suppress VZV EV-mediated HSV-1 reactivation. By defining how non-infectious viral signals alter antiviral immunity and viral latency, this research will uncover a novel mechanism of virus-virus interaction that may contribute to recurrent or more severe herpesvirus infections. Given increasing evidence linking herpesvirus reactivation to neuroinflammatory and neurodegenerative diseases, these findings may identify new therapeutic strategies to protect vulnerable populations and preserve long-term neurological health. Importance of research: this study will systematically evaluate the molecular and cellular homeostatic mechanisms perturbed by VZV and HSV-1 interactions in vivo, contributing to an understanding of immune dysfunction and CNS neuroinvasion. Our interdisciplinary team with expertise in HSV-1 infection and neuroscience (DR. Niemeyer), VZV infection and extracellular vesicle biology (DR. Bubak), and olfactory epithelium pathology (DR. Santoro) is uniquely equipped to complete this study.