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Non-Infectious VZV EVs as a novel modulator of HSV-1 Neurovirulence

Award Number: R21AI200012
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/09/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $429,000 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	1	6/9/2026	NEW	$429,000
														Subtotal = $429,000

Grand Total All Awards = $429,000

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Non-Infectious VZV EVs as a novel modulator of HSV-1 Neurovirulence

Award Number: R21AI200012

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/09/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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