REGULATION OF HSV LATENCY BY POLYCOMB SILENCING - PROJECT SUMMARY/ABSTRACT REACTIVATION OF VIRUSES FROM LAT…

Assistance award details

Assistance award identifier

ASST_NON_R01AI177341_075

FAIN

R01AI177341

Recipient

RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$2,088,140

Period

Jun 7, 2024 – Apr 30, 2029

Fiscal year

2024

Place of performance state

VA

Source file

FY2024_All_Assistance_Full_20261006.zip

Description

REGULATION OF HSV LATENCY BY POLYCOMB SILENCING - PROJECT SUMMARY/ABSTRACT REACTIVATION OF VIRUSES FROM LATENT INFECTION CAN RESULT IN SERIES DISEASE. IN ADDITION, LATENT INFECTIONS ARE A BARRIER TO CURING CERTAIN VIRAL DISEASES. FOR THE PERSISTENT HERPESVIRUS, HERPES SIMPLEX VIRUS (HSV), THE MECHANISMS THAT REGULATE ENTRY OF THE VIRUS INTO A LATENT INFECTION ARE NOT KNOWN. THE FORMATION OF HETEROCHROMATIN ON THE VIRAL GENOME IN NEURONS HAS LONG BEEN HYPOTHESIZED TO CONTRIBUTE TO SUPPRESSING GENE EXPRESSION FOR LATENCY ESTABLISHMENT. HOWEVER, NO FUNCTIONAL STUDIES HAVE YET IDENTIFIED A ROLE FOR HETEROCHROMATIN FORMATION AS A MECHANISM TO PROMOTE ENTRY INTO LATENCY OR MAINTAIN A LATENT INFECTION. THERE ARE MULTIPLE DIFFERENT TYPES OF HETEROCHROMATIN, WHICH DIFFER THEIR MECHANISMS OF GENE SILENCING AND ABILITY TO BE REVERSED FOR GENE EXPRESSION TO TAKE PLACE. OUR OVERALL HYPOTHESIS IS THAT HSV ACTIVELY PROMOTES A TYPE OF HETEROCHROMATIN TO ENABLE BOTH PERSISTENCE AND REACTIVATION. OUR DATA INDICATE THAT THE HISTONE MODIFICATION, H2AK119UB1, IS ENRICHED ON THE HSV GENOME DURING LATENCY. H2AK119UB1 FUNCTIONS TO REPRESS GENE EXPRESSION, BUT IT IS ALSO KNOWN TO BE RAPIDLY REMODELED TO PERMIT GENE EXPRESSION TO TAKE PLACE IN RESPONSE TO CERTAIN STIMULI. IMPORTANTLY, OUR PRELIMINARY DATA INDICATE THAT H2AK119UB1 NEEDS TO BE DEPOSITED ONTO HSV GENOMES TO LATER ENABLE REACTIVATION TO OCCUR. TO UNDERSTAND THE CONTRIBUTION OF H2AK119UB1 TO HSV LATENCY AND REACTIVATION, ALONG WITH THE MECHANISM OF H2AK119UB1 DEPOSITION ON THE GENOME, COMPLEMENTARY IN VITRO AND IN VIVO MODELS OF HSV LATENCY ARE ESSENTIAL. OUR LAB HAS DEVELOPED NOVEL IN VITRO MODEL SYSTEMS TO INVESTIGATE THE MOLECULAR MECHANISMS OF HSV LATENCY ESTABLISHMENT AND REACTIVATION, WHICH WE COMBINE WITH HIGH-RESOLUTION IMAGING TO INVESTIGATE THE ASSOCIATION OF INDIVIDUAL VIRAL GENOMES WITH CHROMATIN-ASSOCIATED PROTEINS. THESE ASSAYS WILL BE COMPLEMENTED WITH EPIGENETIC ASSAYS TO MAP AND QUANTIFY PROTEIN ASSOCIATION WITH