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Defense-in-depth against mucosal HIV clade C invasion

Award Number: P01AI048240
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: 09/30/2000
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Defense-in-depth against mucosal HIV clade C invasion - DESCRIPTION (provided by applicant): Our overall hypothesis is that a defense-in-depth strategy, according to which invading HIV meets not only strong resistance at mucosal frontlines but also at various deeper levels, will greatly improve AIDS vaccine efficacy. Although ~90% of all HIV transmissions occur mucosally, only few studies have focused on the initial events as HIV enters mucosal fluids and crosses epithelial barriers, and on the role of mucosal IgA, which is mostly dimeric (dIgA). We gave the first direct evidence that dIgA is protective when we passively immunized rhesus monkeys (RMs) intrarectally (i.r.) with the monoclonal antibody (mAb) HGN194 as dIgA1, dIgA2, or IgG1 forms; all neutralized the clade C SHIV (SHIV-C) challenge virus equally well in vitro. Given i.r., dIgA2 protected 17% and dIgA1 83% of the RMs against i.r. SHIV-C challenge, respectively; better protection was linked to virion capture and inhibition of transcytosis of cell-free virus. Next, we combined i.v. HGN194 IgG1 with i.r. dIgA2 and compared this combination with i.v. IgG1 nmAb given alone. The latter protected none of the RMs, whereas 100% of the RMs given the IgG1+dIgA2 combination were protected. This strong synergy prompted us to study the interaction between virions, the various Abs in mucosal fluids, and mucus (Project 1). The association of better protection with virion capture, over and above neutralization, led us to postulate that non-neutralizing dIgAs with potent virion-binding ability could prevent mucosal transmission (Project 2). Recently, Darrell Irvine targeted polypeptide antigens and molecular adjuvants to lymph nodes (LNs) by conjugating both to amphiphilic (amph) albumin-binding lipid tails, resulting in efficient albumin-mediated LN uptake. Such amph-vaccines increased T-cell responses 30-fold and humoral responses 20-fold and improved the therapeutic efficacy of cancer vaccines in mice. This P01 seeks to test the hypothesis that immunogens targeted to draining LNs of mucosal virus entry sites will generate strong mucosal IgA defenses as well as IgG and cellular immune responses (Project 3). LN targeting will be followed over time by positron emission tomography (PET) in vaccinated RMs in the Research Imaging Institute (Core D, Drs. Fox & Goins). Cores B (Virology/Immunology; Dr. Sholukh and Lanzavecchia) and C (Primate Studies; Drs. Lakhashe & Gupta) will support all Projects. We seek to test our hypotheses with these Specific Aims: 1. to gain a greater understanding of the initial steps as virus enters the mucosal lumen, interacts with mucus, mucosal Abs, and the cells at and just beyond the epithelial barrier (Project 1; Dr. Hope), 2. to passively administer mAbs with epitope specificities linked to protection and inducible by currently available immunogens, including non-neutralizing epitopes, to examine the interaction of systemically administered IgGs with i.r. administered dIgAs (Project 2; Dr. Ruprecht), and 3. to target vaccine-induced immunity to LNs and mucosal compartments (Project 3; Dr. Irvine).


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 = -$628,357 )
2024	2020	UNIVERSITY OF LOUISIANA AT LAFAYETTE	104 E UNIVERSITY AVE	LAFAYETTE	LA	70503	LAFAYETTE	USA	Allergy and Infectious Diseases Research	000	16	3/21/2024	NON-COMPETING CONTINUATION	-$628,357
														Subtotal = -$628,357

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF LOUISIANA AT LAFAYETTE	104 E UNIVERSITY CIR 3RD FL	LAFAYETTE	LA	70503	LAFAYETTE	USA	Allergy and Infectious Diseases Research	000	16	6/30/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $3,519,079 )
2020	2020	UNIVERSITY OF LOUISIANA AT LAFAYETTE	104 E UNIVERSITY CIR 3RD FL	LAFAYETTE	LA	70503	LAFAYETTE	USA	Allergy and Infectious Diseases Research	002	16	6/30/2020	NON-COMPETING CONTINUATION	$3,519,079
2020	2019	UNIVERSITY OF LOUISIANA AT LAFAYETTE	104 E UNIVERSITY CIR 3RD FL	LAFAYETTE	LA	70503	LAFAYETTE	USA	Allergy and Infectious Diseases Research	001	15	4/14/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,508,927
2020	2018	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	14	4/14/2020	NON-COMPETING CONTINUATION	-$2,508,927
														Subtotal = $3,519,079

Issue Date FY: 2019 ( Subtotal = $4,400,187 )
2019	2019	UNIVERSITY OF LOUISIANA AT LAFAYETTE	104 E UNIVERSITY CIR 3RD FL	LAFAYETTE	LA	70503	LAFAYETTE	USA	Allergy and Infectious Diseases Research	002	15	9/4/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$4,400,187
2019	2018	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	14	9/4/2019	NON-COMPETING CONTINUATION	$0
2019	2018	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	14	8/8/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $4,400,187

Issue Date FY: 2018 ( Subtotal = $4,923,836 )
2018	2018	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	14	7/12/2018	NON-COMPETING CONTINUATION	$4,923,836
														Subtotal = $4,923,836

Issue Date FY: 2017 ( Subtotal = $5,134,226 )
2017	2017	TEXAS BIOMEDICAL RESEARCH INSTITUTE	7620 NW LOOP 410	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	13	6/16/2017	NON-COMPETING CONTINUATION	$5,134,226
2017	2017	TEXAS BIOMEDICAL RESEARCH INSTITUTE	7620 NW LOOP 410	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	13	6/23/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $5,134,226

Issue Date FY: 2016 ( Subtotal = $4,095,518 )
2016	2016	TEXAS BIOMEDICAL RESEARCH INSTITUTE	7620 NORTHWEST LOOP 410	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	12	7/13/2016	COMPETING CONTINUATION	$4,095,518
														Subtotal = $4,095,518

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	10	9/18/2013	NON-COMPETING CONTINUATION	$45,000
2013	2011	TEXAS BIOMEDICAL RESEARCH INSTITUTE	7620 NORTHWEST LOOP 410	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	002	11	9/16/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$510,102
2013	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	10	8/6/2013	NON-COMPETING CONTINUATION	$0
2013	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	10	9/15/2013	NON-COMPETING CONTINUATION	-$555,102
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2009	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	000	8	9/3/2012	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $2,543,677 )
2011	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	10	8/31/2011	NON-COMPETING CONTINUATION	$2,165,710
2011	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	10	9/9/2011	NON-COMPETING CONTINUATION	$377,967
														Subtotal = $2,543,677

Issue Date FY: 2010 ( Subtotal = $2,199,333 )
2010	2010	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	9	7/29/2010	NON-COMPETING CONTINUATION	$2,199,333
														Subtotal = $2,199,333

Issue Date FY: 2009 ( Subtotal = $4,929,533 )
2009	2009	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	8	8/28/2009	NON-COMPETING CONTINUATION	$571,310
2009	2009	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	8	8/3/2009	NON-COMPETING CONTINUATION	$2,384,005
2009	2009	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	002	8	8/28/2009	SUPPLEMENT FOR EXPANSION	$1,974,218
														Subtotal = $4,929,533

Issue Date FY: 2008 ( Subtotal = $2,264,811 )
2008	2008	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	7	8/15/2008	NON-COMPETING CONTINUATION	$2,264,811
														Subtotal = $2,264,811

Issue Date FY: 2007 ( Subtotal = $2,163,226 )
2007	2007	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	6	7/20/2007	COMPETING CONTINUATION	$2,163,226
														Subtotal = $2,163,226

Issue Date FY: 2006 ( Subtotal = $1,150,724 )
2006	2006	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	002	5	9/26/2006	SUPPLEMENT FOR EXPANSION	$1,150,724
														Subtotal = $1,150,724

Issue Date FY: 2004 ( Subtotal = $1,915,349 )
2004	2004	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	001	5	7/15/2004	SUPPLEMENT FOR EXPANSION	$46,107
2004	2004	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	5	6/18/2004	NON-COMPETING CONTINUATION	$1,869,242
														Subtotal = $1,915,349

Issue Date FY: 2003 ( Subtotal = $1,966,903 )
2003	2003	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	4	8/5/2003	NON-COMPETING CONTINUATION	$1,966,903
														Subtotal = $1,966,903

Issue Date FY: 2002 ( Subtotal = $2,272,152 )
2002	2002	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	3	8/19/2002	NON-COMPETING CONTINUATION	$2,248,304
2002	2002	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	001	3	9/5/2002	SUPPLEMENT FOR EXPANSION	$23,848
														Subtotal = $2,272,152

Issue Date FY: 2001 ( Subtotal = $2,111,611 ) (Continued on the next page)
Grand Total All Awards = $46,162,088

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Defense-in-depth against mucosal HIV clade C invasion

Award Number: P01AI048240

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: 09/30/2000

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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