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Directed evolution of a nascent immune function

Award Number: F30AI191743
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/27/2026
PERIOD OF PERFORMANCE END DATE: 09/26/2027

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Directed evolution of a nascent immune function - Project Summary Many endemic viruses, such as HIV-1 and Ebola, hijack the host ESCRT pathway to bud and spread infection. Most host-pathogen interfaces rapidly evolve to evade infection, but ESCRT subunits remain highly conserved across eukaryotes, as adaptations that block viral piracy also disrupt essential cellular functions such as cytokinetic abscission. This evolutionary constraint has allowed a broad class of ESCRT-dependent viruses to bud unchallenged. However, we recently discovered retroCHMP3, a species-specific ESCRT subunit that selectively inhibits ESCRT-dependent viral budding while permitting essential host functions. RetroCHMP3 arose independently in primates (~45 million years ago) and mice (~7 million years ago) as the truncated retrotransposition of the ESCRT subunit, CHMP3. Curiously, previous studies revealed CHMP3 truncation alone is cytotoxic due to dominant-negative inhibition of both host and viral ESCRT functions. These observations raise questions about the selective pressures driving the convergent evolution of retroCHMP3 and how ancestral retroCHMP3 precursors were detoxified while retaining antiviral properties. This project aims to understand the evolutionary mechanism for the detoxification of retroCHMP3, a non- inflammatory restriction factor in its evolutionary infancy. Traditional genetic and mechanistic studies of retroCHMP3 have proved challenging; the sensitivity of ESCRT complexes result in low expression levels of aberrant subunits and inviable stable cell lines and animal models. To overcome these barriers, I’ve established MEDUSA, an experimental evolution system in the budding yeast, Saccharomyces cerevisiae, that allows stable expression and adaptive evolution of mammalian retroCHMP3 under selection. S. cerevisiae is an ideal system to study retroCHMP3 considering its conserved ESCRT machinery, genetic malleability, and tolerance to subunit modifications. My primary hypothesis is that novel immune functions first mitigate cytotoxicity before optimizing antiviral effector properties. Testing this hypothesis will inform us on 1) the adaptive strategies that mitigate its cytotoxicity while preserving its ability to inhibit viral budding, and 2) the compensatory host changes in response to a novel antiviral mechanism. Aim 1 will determine the mechanism of detoxifying retroCHMP3 and its tradeoffs to host function. Aim 2 will determine evolutionary steps for tolerating a nascent ESCRT-dependent restriction factor in a new host. Together, these aims will reveal adaptive pathways for detoxifying emerging immune processes and provide insight into how hosts rapidly evolve in real time to disruptions to core cellular functions. RetroCHMP3 has broad implications for targeted therapeutics for HIV/AIDS and many other viral infections. This fellowship proposal will explore the possibility of a new class of non-inflammatory restriction factor by understanding mechanism for detoxification of a nascent immune pathway and its evolutionary host-pathogen dynamics. As such, this project is ideally suited for a training physician-scientist, as it combines innovative infection biology with comparative and evolutionary studies of emerging immune functions.


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 = $41,123 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	1	3/27/2026	NEW	$40,547
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	001	1	4/2/2026	NEW	$576
														Subtotal = $41,123

Grand Total All Awards = $41,123

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Directed evolution of a nascent immune function

Award Number: F30AI191743

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/27/2026

PERIOD OF PERFORMANCE END DATE: 09/26/2027

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