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Characterization of Epstein-Barr Virus Subversion of the Host SMC5/6 Restriction Pathway

Award Number: R21AI170751
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: 03/09/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Characterization of Epstein-Barr Virus Subversion of the Host SMC5/6 Restriction Pathway - Abstract Epstein-Barr virus (EBV) establishes lifelong infection in 95% of adults worldwide. EBV causes multiple cancers, particularly in hosts with HIV co-infection. EBV is transmitted between hosts through saliva, from which it translocates across the oral cavity and tonsillar epithelium to reach the B-cell compartment. In persons with AIDS, EBV lytic replication causes oral hairy leukoplakia. Upon B-cell infection, the double-stranded DNA (dsDNA) EBV genome is delivered to the nucleus. Much remains to be learned about host pathways that sense incoming EBV genomes, as well as viral genomes in cells undergoing lytic replication, and how EBV interacts with these restriction pathways. We used RNAseq and multiplexed tandem mass tag (TMT) mass spectrometry to create temporal proteomic maps of primary human B-cell infection and of EBV lytic replication. Each highlighted that EBV strongly and specifically downmodulates the SMC5/6 cohesin complex within 1 day of primary B-cell infection, prior to the expression of most viral genes, and again upon lytic reactivation. We identified that the EBV major tegument protein BNRF1 assembles a Cullin-7 based ubiquitin ligase that targets SMC5/6 for proteasomal degradation. In the absence of BNRF1, SMC5/6 shuts down EBV lytic replication compartments and blocks EBV lytic DNA synthesis. CRISPR SMC6 knockout rescues replication compartment formation in Burkitt cells carrying BNRF1 knockout EBV. To our knowledge, SMC5/6 is therefore the first host factor that can restrict EBV replication compartments. However, little is known about how SMC5/6 recognizes EBV genomes as foreign. This important question has remained open across double stranded DNA viral genomes, where focus has instead been on how viruses evade SMC5/6. Our central hypothesis is that the SMC5/6 cohesin recognizes and restricts viral non-B-form DNA structures necessary for EBV latency establishment and lytic DNA replication in a manner modulated by BNRF1. Our Aims are to (1) Identify how SMC5/6 senses and restricts latent EBV DNA in newly infected cells and to (2) Identify how SMC5/6 senses and restricts lytic EBV DNA upon reactivation. Collectively, these studies address the key open question about how SMC5/6 functions in order to discriminate viral from host DNA, which has remained nearly unstudied despite growing recognition of SMC5/6 roles in regulation of double stranded viral DNA.


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: 2025 ( Subtotal = -$36,971 )
2025	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	7/1/2025	NON-COMPETING CONTINUATION	-$36,971
														Subtotal = -$36,971

Issue Date FY: 2024 ( Subtotal = $268,500 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	4/2/2024	NON-COMPETING CONTINUATION	$268,500
														Subtotal = $268,500

Issue Date FY: 2023 ( Subtotal = $223,750 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	3/9/2023	NEW	$223,750
														Subtotal = $223,750

Grand Total All Awards = $455,279

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Characterization of Epstein-Barr Virus Subversion of the Host SMC5/6 Restriction Pathway

Award Number: R21AI170751

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: 03/09/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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