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Investigating VICE domain functions tied to altered ribosome localization and translational flux during HSV-1 infection

Award Number: F31AI191634
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Investigating VICE domain functions tied to altered ribosome localization and translational flux during HSV-1 infection - Herpes simplex virus type-1 (HSV-1) initiates cell-wide competition for essential resources and cellular factors, remodeling the nucleus by requisitioning histones and RNA polymerases, reprogramming splicing complexes, and dissolving the nucleolus, a site responsible for the bulk of ribosome biogenesis. To globally capture protein- protein interactions underlying this remodeling we developed and implemented a hybrid mass spectrometry approach using thermal proximity coaggregation profiling with nuclear-cytoplasmic fractionation. Analysis revealed the accumulation of dozens of cellular chaperones in the nucleus throughout infection, suggestive of the formation of Virus Induced Chaperone Enriched (VICE) domains. VICE domains are a unique, yet nebulous feature of HSV-1 infection whose overall composition and functional significance are not well understood. We therefore leveraged our subcellular thermal profiling results to gain further insight into the composition and properties of VICE domains. Through examination of proteins exhibiting HSV-1 dependent interactions with chaperone proteins in the nucleus, we discovered that ribosome biogenesis factors are recruited to VICE domains, a finding we expanded upon to identify VICE-driven recruitment of both nascent nuclear and mature cytoplasmic ribosomal proteins as well as ribosomal RNA. This correlated with substantial remodeling of ribonucleoprotein signatures within the nucleus and intense concentration of nascent proteins within VICE domains. These preliminary findings implicate ribosome remodeling, translational capacity, and altered proteostasis in the functional significance of VICE domains. My central hypothesis is that subcellular rerouting of translational flux via VICE domains is an evolved strategy to outcompete host cells for proteostatic resources. In Aim 1, I will incorporate orthogonal methods in proteomics and transcriptomics to measure VICE domain components in a cross-sectional and flux-dependent manner, using this information for bioinformatic analysis to define structure or sequence-specific drivers of VICE domain recruitment and testing whether VICE sequestration of proviral factors can synthetically restrict HSV-1 replication. In Aim 2, I will employ a complementation strategy modulating VICE domain formation to interrogate how VICE-driven regulation of proteostasis contributes to HSV-1 replication and spread. Overall, this proposal takes an integrated approach using proteomics, transcriptomics, machine learning-assisted bioengineering, confocal microscopy, and virology to elucidate the functional significance of a unique and under-characterized feature of HSV-1 biology with implications for fundamental biological processes in translation and proteostasis. This work will take place at Princeton University in the laboratory of Dr. Ileana Cristea, an internationally renowned expert in proteomics and virology with a strong track record training successful academic scientists. My professional and research development will by supported by career development and writing workshops offered at Princeton, presentation of research at conferences, and preparation of manuscripts.


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 = $34,114 )
2026	2026	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	2	3/31/2026	NON-COMPETING CONTINUATION	$33,538
2026	2026	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	001	2	4/2/2026	NON-COMPETING CONTINUATION	$576
														Subtotal = $34,114

Issue Date FY: 2025 ( Subtotal = $33,538 )
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	002	1	7/24/2025	NEW	$564
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	001	1	3/24/2025	NEW	$0
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	1	3/24/2025	NEW	$32,974
														Subtotal = $33,538

Grand Total All Awards = $67,652

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Investigating VICE domain functions tied to altered ribosome localization and translational flux during HSV-1 infection

Award Number: F31AI191634

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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