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Activation of type I interferon production in human immune cells by cell-to-cell transmission of HIV-1

Award Number: R15AI192135
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: 05/06/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Activation of type I interferon production in human immune cells by cell-to-cell transmission of HIV-1 - ABSTRACT Type I interferon (IFN) is an important cytokine that not only functions as host innate immune response against infection but also regulates inflammation and immunopathogenesis process. IFN production mediated by cGAS/STING signaling pathway, which senses cytosol DNA, is one of fundamental systems found in a variety of viral infections. However, mechanisms of how HIV-1 infection induces production of IFN in immune cells has been incompletely understood for decades. Clinical studies have demonstrated elevated IFN activity in people living with HIV-1. In similar, persistent IFN expressions were found in HIV/AIDS animal models. However, in vitro studies using cell-free HIV-1 viruses reported poor induction of IFN production triggered by cGAS/STING signaling pathway. Interestingly, in a pilot study, we found that HIV-1 cell associated infection, a mode of viral transmission through direct cell to cell contact that yields rapid virion transfer and much efficient replication, activated IFN expression by triggering cGAS-STING signaling pathway in cultured MT2 cells. Therefore, in this study, we hypothesize that cell-to-cell transmission of HIV-1 activates productions of IFNs and inflammatory cytokines by inducing cGAS/STING pathways. We have developed two cell based models to study cell-to-cell transmission of HIV-1 independent of cell free virus infection in both cultured and primary human immune cells.We propose to test our hypothesis by two specific aims. Aim 1. To investigate whether HIV-1 cell-to-cell transmission activates IFN production by inducing cGAS/STING/IRF-3 pathway. We will investigate and confirm the activation of this pathway specifically by cell associated infection. We will further verify that cGAS is the sensor of this pathway activation and identify factors that triggers this activation under unique virological and cellular environments during cell associated trasmission of HIV-1. Aim 2. To investigate whether HIV- 1 cell-to-cell transmission triggers cGAS/STING/NF-κB pathway. We will examine changes in status of this signaling pathway activation after cell-to-cell transmission of HIV-1. We will also investigate if cell associated infection reactivates HIV-1 in latency through upregulating NF-κB. Understanding the role of HIV- 1 cell-to-cell transmission in the activation of IFN with well characterized signaling pathways will represent a new way to fulfill our understanding in the pathogenesis of HIV infection as well as providing a potential guide to therapeutic approaches. This study will also provide great opportunity of research collaborations and extensive learning experience for students at ACPHS.


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 = $479,925 )
2025	2025	ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES	106 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Allergy and Infectious Diseases Research	000	1	5/7/2025	NEW	$479,925
														Subtotal = $479,925

Grand Total All Awards = $479,925

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Activation of type I interferon production in human immune cells by cell-to-cell transmission of HIV-1

Award Number: R15AI192135

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: 05/06/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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