Monday, December 15, 2025 12/15/2025

(PQ1) HIV-infected T-cell exosomes in lung cancer progression

Award Number: R01CA250067
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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(PQ1) HIV-infected T-cell exosomes in lung cancer progression - Project Summary/Abstract Lung cancer (LCa) is the second most common malignancy in the US with about 222,500 new cases and 155,900 deaths each year. HIV-infected individuals and AIDS patients have increased relative risk of LCa by 250% after controlling for other potential risk factors. LCa in HIV+ people under antiretroviral therapy (ART) is diagnosed at younger ages than those in the general population. This trend in the ART era is implicitly attributed to prolonged life span and aging of the population. The success of new approaches to control lung tumorigenesis in the population is contingent to identify HIV-specific mechanisms that facilitate the tumor progression and metastasis. HIV-infected T cells release a variety of immunologically active exosomes, small vesicles of endocytic origin, to influence intercellular communication and material transfer at both local and distant sites, thus potentially contribute to enhanced risk for tumorigenesis. Our preliminary studies have found that exosomes secreted by HIV-infected T cells and purified from the blood of lung cancer patients of people living with HIV (PLWH) significantly stimulated lung cancer cell proliferation. HIV-associated exosomes induced MAP kinase ERK1/2 activation via interaction with epidermal growth factor receptor (EGFR) and the toll like receptor 3 (TLR3). Mechanistically, the HIV trans-activation response (TAR) element RNA, which exists in excess of other HIV RNAs in exosome from HIV-infected T cells, is responsible for enhanced cancer cell proliferation and proto-oncogene expression. We have established a bone marrow transplant (BMT) mouse model in which lethally-irradiated FVB mice were grafted with syngeneic bone marrow cells of Tg26 HIV- transgenic mice. Growth and metastasis of allografts LCa cells were significantly enhanced in grafted mice containing HIV+ bone marrow cells compared with that in non-grafted control mice. However, reconstitution of circulating immune cells and bone marrow remained the same between two groups of mice, suggesting that TAR RNA-bearing exosomes from reconstituted HIV+ immune cells may promote LCa progression in the BMT model. Taken together, these data lead us to hypothesize that TAR RNA-bearing exosomes from HIV-infected immune cells promote lung cancer growth and progression and that controlling release of the exosomes or directly targeting the TAR RNA may serve as an adjuvant for prevention and treatment of lung cancer in HIV- infected individuals. To test this hypothesis, we will first delineate the mechanism by which HIV-1-infected T- cell exosomes stimulate LCa growth and progression in vivo using the BMT model. The potentials for therapeutic intervention of LCa promotion by HIV will be examined through inhibition of exosome production and neutralization of TAR RNA. Finally, we will comprehensively examine the HIV-positive exosomal membrane proteins for interaction with EGFR and HIV-specific cargo components in the circulation using our novel EV-omics approach. Completion of the proposed studies will shed light on the mechanisms underlying HIV-mediated promotion of LCa and lay a foundation for therapeutic intervention of non-AIDS-defining cancers.


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 = -$66,569 )
2026	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	5	12/2/2025	NON-COMPETING CONTINUATION	-$66,569
														Subtotal = -$66,569

Issue Date FY: 2024 ( Subtotal = $703,784 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	5	6/6/2024	NON-COMPETING CONTINUATION	$703,784
														Subtotal = $703,784

Issue Date FY: 2023 ( Subtotal = $700,187 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	4	6/13/2023	NON-COMPETING CONTINUATION	$700,187
														Subtotal = $700,187

Issue Date FY: 2022 ( Subtotal = $774,099 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	3	6/30/2022	NON-COMPETING CONTINUATION	$774,099
														Subtotal = $774,099

Issue Date FY: 2021 ( Subtotal = $756,944 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	2	6/22/2021	NON-COMPETING CONTINUATION	$756,944
														Subtotal = $756,944

Issue Date FY: 2020 ( Subtotal = $732,429 )
2020	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	1	6/25/2020	NEW	$732,429
														Subtotal = $732,429

Grand Total All Awards = $3,600,874

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(PQ1) HIV-infected T-cell exosomes in lung cancer progression

Award Number: R01CA250067

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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