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Modulation of MHC-I antigen presentation in immune surveillance and evasion by viruses and tumors

Award Number: DP2AI200959
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: 08/06/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Modulation of MHC-I antigen presentation in immune surveillance and evasion by viruses and tumors - Project Summary The adaptive immune system can detect and eliminate diseased cells through the presentation of peptide antigens on the cell surface by major histocompatibility complex class-I (MHC-I) molecules. This process is critical for controlling viral infection and limiting tumor growth, yet little is known about how cells decide what peptides to display to trigger a rapid and robust immune response. This knowledge gap reflects both the extraordinary complexity of antigen processing and the lack of tools to directly observe the process, limiting our efforts to harness adaptive immunity against viral infection, cancer, and autoimmunity. This proposal describes a comprehensive mechanistic framework to dissect, visualize, and manipulate the dynamic macromolecular machines important for MHC-I antigen processing and presentation. In previous work, I established a biochemical and structural platform to interrogate the first step of antigen presentation. Here, I expand upon this foundation and describe an innovative chemical biology strategy to map the entire route of peptide antigen loading onto MHC-I both in cells and in reconstituted systems. Using this approach together with advanced biochemical, biophysical, and structural methods such as single-particle cryo-electron microscopy, these strategies will provide a complete molecular view of the dynamic macromolecular machines that regulate MHC-I assembly in native-like environments. In parallel, we will explore the diverse and largely uncharacterized strategies viruses, including herpesviruses and poxviruses, use to disrupt antigen presentation. We will then leverage these mechanisms as natural blueprints to engineer synthetic immunomodulators as a new approach to immunotherapy. Such tools have the potential to enhance the immune response against infections and tumors or suppress aberrant immune activation in the context of autoimmune diseases. This high-risk high-reward research represents a unique integration of chemical biology, structural biology, virology, and protein engineering that will deepen our fundamental understanding of antigen presentation regulation, reveal unexpected strategies of viral immune evasion, and establish new tools for therapeutic immune modulation.


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 = $508,500 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	8/5/2026	NEW	$508,500
														Subtotal = $508,500

Grand Total All Awards = $508,500

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Modulation of MHC-I antigen presentation in immune surveillance and evasion by viruses and tumors

Award Number: DP2AI200959

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: 08/06/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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