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The Cell Biology of HIV-1 Genome Trafficking

Award Number: R01AI110221
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: 07/01/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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The Cell Biology of HIV-1 Genome Trafficking - PROJECT SUMMARY / ABSTRACT There are more than 38 million people still living with HIV-1 infection worldwide, and more than 1.1 million in the United States alone. HIV-1 acute infection and latency reversal are both dependent on the expression of full- length unspliced viral RNAs (US-vRNAs) that serve dual roles in the cytoplasm as either (1) viral mRNAs encoding Gag and Gag-Pol proteins that drive virus particle assembly or (2) viral RNA genome substrates bound by Gag/Gag-Pol for packaging into virions. This project combines live cell and super-resolution imaging, biochemical assays, and other research tools to address key foundational issues in HIV-1 US-vRNA subcellular trafficking with the goal of exposing new virus and cell biology of potential relevance to novel antiviral strategies. Aim 1 is to determine why HIV-1 evolved to exploit a highly unconventional RNA export machinery regulated by Exportin-1 (XPO1, also known as CRM1) for US-vRNA nucleocytoplasmic transport, and how cooperativity- based RNA-protein interactions regulated by the viral Rev protein serve to activate this pathway. Our preliminary data and prior studies support a model wherein Rev multimerization on the US-vRNA’s Rev response element (RRE) forms a multi-NES complex needed to recruit at least two XPO1 proteins for activation of US-vRNA nuclear export. Moreover, live cell imaging has indicated that US-vRNA transcripts first build up in the nucleus prior to exhibiting “burst-like” nuclear export kinetics when virion production is initiated. We will test the hypothesis that burst export is explained HIV-1 US-vRNAs, Rev, and XPO1 interact in a stepwise manner to ultimately link viral transcription to nuclear pores, thereby upregulating late-stage delivery of US-vRNAs to the cytoplasm. To this end, we will carefully dissect Rev and the US-vRNA’s transitional stages over space and time in single cells using a combination of live cell imaging and an innovative “cell expansion” superresolution light microscopy technique. Our goal is to precisely define the subnuclear sites of Rev-US-vRNA and Rev-XPO1 interactions and understand the effects of prescribed perturbations to these essential processes, including a profound cell-specific block to HIV-1 US-vRNA nuclear export observed in mice and other rodents. For Aim 2, we will extend these studies to the cytoplasm, again using live cell and super-resolution imaging in combination with RNA capture proteomics to test the hypotheses that Rev-dependent nuclear export licenses viral RNAs for (1) enhanced stability in the cytoplasm and (2) preferred delivery to sites of genome packaging into virions. These experiments will take advantage of newly described mutant forms of HIV-1 that allow us to, for the first time, study US-vRNAs that are specifically programmed for either translation or packaging fates. We will also exploit these comparative conditions to identify new host proteins/pathways specifically associated with US-vRNA translation vs. packaging. Collectively, these studies will provide new mechanistic insights into the viral and cellular machines that drive HIV-1 genome trafficking and advance the development of new technologies for studying HIV-host interactions.


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: 2025 ( Subtotal = $265,211 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	11	6/25/2025	COMPETING CONTINUATION	$376,863
2025	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	10	2/13/2025	NON-COMPETING CONTINUATION	-$111,652
														Subtotal = $265,211

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	10	8/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $382,090 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	10	5/26/2023	NON-COMPETING CONTINUATION	$382,090
														Subtotal = $382,090

Issue Date FY: 2022 ( Subtotal = $382,090 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	9	5/18/2022	NON-COMPETING CONTINUATION	$382,090
														Subtotal = $382,090

Issue Date FY: 2021 ( Subtotal = $381,991 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	8	5/11/2021	NON-COMPETING CONTINUATION	$381,991
														Subtotal = $381,991

Issue Date FY: 2020 ( Subtotal = $380,900 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	002	7	5/21/2020	NON-COMPETING CONTINUATION	$380,900
2020	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	6	2/4/2020	COMPETING CONTINUATION	$85,880
2020	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	5	2/4/2020	NON-COMPETING CONTINUATION	-$85,880
														Subtotal = $380,900

Issue Date FY: 2019 ( Subtotal = $387,292 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	6	6/5/2019	COMPETING CONTINUATION	$387,292
2019	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	5	6/4/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,292

Issue Date FY: 2018 ( Subtotal = $330,545 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	5	12/13/2017	NON-COMPETING CONTINUATION	$330,545
														Subtotal = $330,545

Issue Date FY: 2017 ( Subtotal = $330,545 )
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	4	12/22/2016	NON-COMPETING CONTINUATION	$330,545
														Subtotal = $330,545

Issue Date FY: 2016 ( Subtotal = $330,545 )
2016	2016	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	3	12/7/2015	NON-COMPETING CONTINUATION	$330,545
														Subtotal = $330,545

Issue Date FY: 2015 ( Subtotal = $330,545 )
2015	2015	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	2	12/8/2014	NON-COMPETING CONTINUATION	$330,545
														Subtotal = $330,545

Issue Date FY: 2014 ( Subtotal = $330,545 )
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	1	1/15/2014	NEW	$297,491
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	1	6/13/2014	NEW	$33,054
														Subtotal = $330,545

Grand Total All Awards = $3,832,299

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The Cell Biology of HIV-1 Genome Trafficking

Award Number: R01AI110221

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: 07/01/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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