Determinants of HIV-1 innate immune sensing and its role in shaping the lymphoid environment

Active Project Grant Awarded Last action

Award ID
R01AI177265
Recipient
Awarding agency
Obligated
$4,370,662

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 84% complete
Place of performance
La Jolla, CA 92037, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
HIV-1 has a low transmission rate and most new infections via the mucosal route are initiated by a single variant out of a viral quasispecies. Recent studies in non-human primates found that mucosal transmission foci contain infected dendritic cells, and IT remains to be determined why their innate responses sometimes fail to prevent viral spread. Selective advantages that allow a virus to cross a recipient's mucosal barrier include the ability to evade restriction factors and suppress innate antiviral responses. Various HIV-1 proteins participate in these evasion tactics, including the viral capsid. After entry, the capsid binds cellular factors necessary for its transit to the nucleus and synthesis of viral DNA, while repelling restriction factors and specialized innate sensors. Over the years, we have studied several innate sensors and, most recently, our studies have focused on HIV-1- dependent activation of cyclic gamp synthase (CGAS), a cytosolic DNA sensor. We discovered that polyglutamine binding protein 1 (PQBP1) is an adaptor required for CGAS sensing of HIV-1 DNA. PQBP1 binds to the HIV-1 capsid, thereby authenticating IT as a danger signal, then recruits CGAS to the capsid as IT begins to disassemble and reveal the nascent viral DNA. We assume that PQBP1 transfers CGAS to the emerging DNA by a "bait and switch" mechanism, resulting in CGAS activation and downstream gene expression. We identified both naturally occurring and genetically engineered capsid variants that activate CGAS to different levels, suggesting that capsid structure is a key determinant of this innate pathway. A critical GAP in our knowledge that will be addressed by this project is how PQBP1-capsid interactions and molecular rearrangements control the strength of the CGAS signal (aims 1 and 2). The CGAS pathway is predominanuy responsible for innate immune responses triggered by HIV-1 infection of dendritic cells, resulting in expression of antiviral factors and type I interferons as well as proinflammatory cytokines. Paradoxically, while induction of antiviral genes inhibits replication, proinflammatory cytokines can activate resting CD4+ T cells and may promote infection. We hypothesize that the strength of the CGAS signal activated by HIV-1 can tip the balance from antiviral to proinflammatory responses, thereby contributing to successful transmission. The same mechanism may also be activated in other lymphoid tissues, downstream of the initial transmission event, and may determine the course of reservoir seeding. Another critical GAP in our knowledge that will be addressed by this project is how the level of CGAS activation drives the balance between antiviral and proinflammatory responses and the role of the HIV- 1 capsid in determining its magnitude, both in vitro and in vivo (aim 3). Our findings will provide insight into the molecular events that determine the outcome of viral exposure, and these same mechanisms could also contribute to HIV-1 pathogenesis. Additionally, our findings will provide important guidance for the design of appropriate adjuvant and vaccine strategies for HIV-1 and other pathologies that involve the CGAS pathway.

Transactions

Action Obligated Date
Amendment $840,133
Amendment $846,223
Amendment $839,256
Amendment $922,525
Original award $922,525

Subawards

Subrecipient Amount Awarded
Emory University Yr4 funding $69,233
Rush University Medical Center Award has been revised to reflect Year 4 funding. Year 4 Period of Performance is 07/01/2026 - 06/30/2027 $108,066
University Of Utah Award has been revised to reflect Year 4 funding. $123,200
Northwestern University $128,000
The Johns Hopkins University Amendment has been revised to reduce funding in Year 1 by $60,000. -$60,000
Northwestern University Award revisedd to reflect Year 3 Funding $128,000
University Of Utah Award revised to reflect Year 3 funding. $123,200
Emory University Award revised to reflect Year 3 Funding $61,143
Rush University Medical Center Award revised to reflect Year 3 funding $106,650
Rush University Medical Center Award has been revised to reflect Year 3 funding. $106,650
Emory University Yr2 funding $58,688
Rush University Medical Center Award has been revised to reflect Year 2 funding. $106,650
Northwestern University Award has been revised to reflect Year 2 funding $128,000
University Of Utah $123,200
Rush University Medical Center Determinants of HIV-1 innate immune sensing and its role in shaping the lymphoid environment. $103,456
Northwestern University Award a cost reimbursable subaward. $128,170
University Of Utah Determinants of HIV-1Innate Immune Sensing and its role in shaping the Lymphoid Environment $129,200
Emory University Determinants of HIV-1 innate immune sensing and its role in shaping the lymphoid environment $58,533
Show all 18

Quick answers

Who received award R01AI177265?

R01AI177265 was awarded to Scripps Research Institute by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on July 12, 2023.

How much is award R01AI177265 worth?

$4,370,662 has been obligated on R01AI177265.

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