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Elucidating the role of B cell mediated trans infection in the establishment of the latent HIV-1 reservoir

Award Number: R01AI162615
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: 08/02/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Elucidating the role of B cell mediated trans infection in the establishment of the latent HIV-1 reservoir - SUMMARY HIV-1 can proliferate through both the release of cell-free particles (cis-infection) and by cell-to-cell transmission (trans-infection). Prior studies have shown that HIV-1 trans-infection: (i) is significantly more eﬃcient than cis-infection; (ii) can efficiently infect resting CD4+ T cells, which are inherently resistant to cis- infection; and (iii) is largely insensitive to inhibition by antiretroviral therapy (ART). Consequently, HIV-1 trans- infection is thought to play a key role in the pathogenesis of HIV-1 infection. Direct evidence of HIV-1 trans- infection in vivo, however, is lacking! Our group was the first to demonstrate that activated B cells express the C-type lectin DC-SIGN and have the ability to sequester and then efficiently transfer HIV-1 to bystander CD4+T cells. B cells have a greater capacity to transfer HIV-1 to CD4+ T cells than other antigen presenting cells, including dendritic cells (DCs) and macrophages. We recently found that B cells, but not immature or mature DC, also have the unique ability to efficiently trans-infect CD4+ naïve (TN) cells – which do not express the CCR5 receptor – with R5-tropic HIV-1. Importantly, we have reported that B cells from HIV-infected nonprogressors (NPs, individuals who control viremia in the absence of ART) do not support HIV-1 trans- infection of CD4+ T cells. Consistent with these findings, purified CD4+ TN cells isolated from NPs harbor a very small (or even negligible) reservoir of total HIV-1 DNA, compared to ART-treated progressors. In this R01 application, our overarching hypothesis is that B lymphocyte-mediated cell-to-cell HIV-1 trans-infection contributes to the establishment and replenishment of the latent viral reservoir in resting CD4+ T cells, in particular CD4+ TN and T follicular helper cells. We propose to use novel state-of the-art approaches to investigate this hypothesis, and expect to provide the first evidence that HIV-1 trans-infection plays a key role in viral pathogenesis.


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 = $728,506 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	4	9/11/2025	NON-COMPETING CONTINUATION	$728,506
														Subtotal = $728,506

Issue Date FY: 2024 ( Subtotal = $728,506 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	3	7/12/2024	NON-COMPETING CONTINUATION	$728,506
														Subtotal = $728,506

Issue Date FY: 2023 ( Subtotal = $728,506 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	7/18/2023	NON-COMPETING CONTINUATION	$728,506
														Subtotal = $728,506

Issue Date FY: 2022 ( Subtotal = $778,686 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	8/2/2022	NEW	$778,686
														Subtotal = $778,686

Grand Total All Awards = $2,964,204

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Elucidating the role of B cell mediated trans infection in the establishment of the latent HIV-1 reservoir

Award Number: R01AI162615

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: 08/02/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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