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Innate Immune Surveillance of HIV-1 During Transmission and Systemic Infection

Award Number: R01AI127302
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: 02/28/2017
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Innate Immune Surveillance of HIV-1 During Transmission and Systemic Infection - Project Summary Innate immune responses represent one of the first and most potent lines of defense against infection. Importance of this surveillance network is underscored by the numerous mechanisms that pathogens have evolved to counteract and evade these responses. The success of the immediate innate immune response relies on the recognition of conserved structures, termed pathogen associated molecular patterns (PAMPs), commonly present in microbes but not in the host. Pattern recognition receptors (PRRs) act as microbial sensors for the host. The sensing of PAMPs by host PRRs initiate the induction of several intracellular signaling events, triggering the expression of cytokines and interferons, which can govern potent restrictors of pathogen infection. In this application, we propose to pursue the hypothesis that a robust innate immune recognition and response to HIV-1 exposure, likely elicited from abortive infection of myeloid cells, rises from the activation of key pattern recognition receptor (PRR) pathways and results in a localized antiviral environment that markedly decreases the likelihood of CD4+ T cell infection and subsequent spread of infection, both in the mucosa and during peripheral infection. The cGAS cytoplasmic DNA sensing pathway, which is particularly active in myeloid cells, has recently been identified as a key sensor for reverse transcribed HIV-1 DNA. Activation of this and potentially other PRR-governed pathways promote the secretion of interferons (IFNs) leading to the transcription of hundreds of interferon-stimulated genes (ISGs), some of which contribute to suppression of HIV-1 replication. Recently, we have reported the identification PQBP1 as a critical component in the recognition of early HIV-1 nucleic acid products required for activation of the cGAS DNA sensing pathway, resulting IFN induction in HIV-infected myeloid cells. Here, we propose to investigate in more detail the regulation of this novel sensing circuit, including understanding the features and accessibility of the HIV-1 PAMP, its downstream regulation, and its impact in HIV-1 transmission. A better understanding of the innate response circuitry that senses HIV-1 infection is likely to enable the development of novel therapeutic interventions against systemic HIV-1 infection, and the illumination of the molecular basis of a protective mucosal innate response to HIV-1 will be critical in next generation vaccine and adjuvant design.


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: 2024 ( Subtotal = -$8,890 )
2024	2021	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	12/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$8,890
														Subtotal = -$8,890

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	5/17/2023	NON-COMPETING CONTINUATION	-$1
2023	2021	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	6	5/17/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $82,007 )
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	004	6	7/13/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$41,208
2022	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	003	5	7/13/2022	NON-COMPETING CONTINUATION	$32,331
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	6	3/3/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$420,740
2022	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	5	3/3/2022	NON-COMPETING CONTINUATION	-$329,856
2022	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	2/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $82,007

Issue Date FY: 2021 ( Subtotal = $860,576 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	1/15/2021	NON-COMPETING CONTINUATION	$860,576
														Subtotal = $860,576

Issue Date FY: 2020 ( Subtotal = $860,913 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	1/21/2020	NON-COMPETING CONTINUATION	$860,913
														Subtotal = $860,913

Issue Date FY: 2019 ( Subtotal = $861,268 )
2019	2019	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	1/22/2019	NON-COMPETING CONTINUATION	$861,268
														Subtotal = $861,268

Issue Date FY: 2018 ( Subtotal = $861,892 )
2018	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	1/23/2018	NON-COMPETING CONTINUATION	$861,892
														Subtotal = $861,892

Issue Date FY: 2017 ( Subtotal = $910,053 )
2017	2017	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	2/28/2017	NEW	$910,053
														Subtotal = $910,053

Grand Total All Awards = $4,427,819

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Innate Immune Surveillance of HIV-1 During Transmission and Systemic Infection

Award Number: R01AI127302

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: 02/28/2017

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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