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Role of the BKV polyomavirus large T antigen IDR in productive infection.

Award Number: R21AI193361
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: 08/17/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Role of the BKV polyomavirus large T antigen IDR in productive infection. - PROJECT SUMMARY/ABSTRACT Fourteen members of the polyomaviridae are associated with humans and several of them establish lifelong chronic infections. Among these is Human Polyomavirus 1, or BKV. Nearly the entire human population is seropositive for BKV, yet in most individuals there are no symptoms. Occasionally, BKV can be detected in the urine of healthy individuals, but this is transient and rare. However, BKV can cause serious diseases in immunosuppressed individuals, especially transplant patients. During nephropathy BKV infected cells can be detected in the urinary tract, especially the renal proximal tubule epithelia (RPTE) and patients secrete high levels of BKV in their urine. Two important unknowns limit the ability to design therapies that limit the high level productive infection that leads to BKV-associated diseases. First, where is BKV in healthy individuals? The virus or its genome must persist in an as yet unidentified cell type(s). Second, what regulates the switch from a low level persistent infection in healthy individuals to a full productive infection associated with disease? We will test hypothesis that BKV establishes latency its permissive cell type, RPTE. In this model latency is the normal consequence of BKV infection of healthy RPTE. However, during acute or chronic kidney disease some RPTE enter a stressed state, in some cases reentering the cell cycle. In current models, the BKV productive cycle initiates with the infection of healthy RPTE. LT then drives the cells into S phase and redirects the cellular DNA replication apparatus to the viral genome. We hypothesize an alternative model in which the infection of healthy growth-arrested cells leads to a latent or very low level persistent infection. Infected cells retain the viral genome with little or no viral transcription. Should a latently infected cells become stressed and enter the cell cycle, LT then captures cellular DNA replication proteins and redirects them to the viral origin of replication and the productive cycle ensues. We further hypothesize that the key regulator of the latency to productive switch is LT itself. High levels of LT favor its association with the cellular replication apparatus and productive infection. Low levels of LT favor its association with factors that repress viral gene expression and/or decrease LT stability. Consistent with this hypothesis, we have found that, while infection of subconfluent cultured RPTE results in a productive infection, BKV gene expression is severely repressed in growth-arrested highly dense cultures. The repressed viral genome persists in at least a subset of these cells since the later addition of growth factors rescues a productive infection. We have generated a BKV mutant (5As) that expresses highly elevated levels of LT and grows faster and to higher titer in cell culture than wild type BKV. Using these tools, we will determine the number of cells harboring BKV genomes, and the number of viral genomes in each cell, and determine how LT levels are regulated to govern the latent to productive switch. We will identify the mechanisms that result in LT overexpression and thereby favor productive infection.


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 = $238,500 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	8/17/2026	NEW	$238,500
														Subtotal = $238,500

Grand Total All Awards = $238,500

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Role of the BKV polyomavirus large T antigen IDR in productive infection.

Award Number: R21AI193361

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: 08/17/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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