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Visualization of nuclear pore passage of the HIV-1 capsid

Award Number: R01AI194916
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: 07/31/2031

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Visualization of nuclear pore passage of the HIV-1 capsid - PROJECT SUMMARY: HIV/AIDS remains a global epidemic, with 1.5 M infections per year globally, more than 40 years after the initial discovery of the virus. To find new avenues for antiviral therapies, it is important to understand the molecular and structural details of the entire process that the virus uses to enter and traffic the cell. This project is focused on visualizing how the HIV-1 capsid traverses the nuclear pore complex (NPC), a critical step on its journey to the nucleus for uncoating, reverse transcription, and integration. A series of recent publications, including our own, R21-funded work, suggest that the capsid can translocate through the NPC and that uncoating likely takes place inside of the nucleus. This dogmatic shift came about as data showed that the NPC can, in fact, accommodate an assembled HIV-1 capsid, while it was previously perceived to be too narrow. We and others have now established that the assembled capsid can translocate through an NPC, by mimicking nuclear transport receptors. Visualizing HIV-1 capsid transport through the NPC promises to reveal whether and how the HIV-1 capsid, or the NPC, or both, undergo structural changes as part of the process. This research should also provide insight into whether the NPC plays an active role in preparing the HIV-1 capsid for disassembly. In Aim 1, we will first generate nanobodies against the HIV-1 capsid as a trapping agent. These nanobodies will be thoroughly structurally characterized and examined for their influence on HIV-1 capsids integrity and functionality. In Aim 2, we will use an in-vitro system to measure the interaction between capsids and capsid-like particles with FG-hydrogels. This will enable us to find favorable conditions and valuable HIV-1 capsid mutants for structural analysis. In Aim 3, we will determine the structure of HIV-1 capsids transported through the NPC using cryo-electronmicroscopy. This is a formidable challenge due to the dynamic properties of the NPC and the flexibility of the HIV-1 capsid. However, how NPC and HIV-1 capsid influence each other will be important for understanding how the infection may be stopped at this key juncture.


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 = $553,136 )
2026	2026	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	8/17/2026	NEW	$553,136
														Subtotal = $553,136

Grand Total All Awards = $553,136

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Visualization of nuclear pore passage of the HIV-1 capsid

Award Number: R01AI194916

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: 07/31/2031

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