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Determinants of HIV transmission fitness

Award Number: R01AI049170
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: 09/27/2002
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Determinants of HIV transmission fitness - Hypothesis: A minimal glycan shield with specific sugar composition on the envelope glycoprotein (Env) of HIV- 1 may be necessary for establishing new infections. In the HIV “selected” for a new infection, glycan content/composition on Env could differ based on the mode and receptacle of transmission (e.g. rectal, penile, foreskin, vaginal, and cervical tissue in sexual transmission) as well as the cytokine/chemokine milieu and microbiome. Understanding glycan composition on the transmitted HIV-1 in these microenvironments would improve the design and effectiveness of humoral-based HIV-1 vaccine. For the past 15 years, this R01 has compared HIV disease parameters to replicative HIV fitness in T cells, macrophages, dendritic cell cocultures, and various ex vivo, non-mucosal tissues. We have shown that competitive replicative fitness of patient-derived HIV is a surrogate of pathogenesis and in the absence of treatment, was a strong correlate of disease progression. However, our published work indicates that “pathogenic” and “transmission” fitness of primary HIV-1 isolates are quite distinct. Using varying conditions with human explant penile and endocervical (EnC) tissues exposed to over 20 different mixtures of HIV-1 derived from acute and chronic disease, we now have a clearer picture of factors impacting HIV transmission. We observed “trapped” replication of chronic HIV-1 in mucosal (penile and cervical) tissue while the acute HIV-1 isolates were carried through the tissue (possibly via DCs) to infect Th17 or Th1 CD4+ T cells. HIV-1 that “escapes” mucosal tissues typically have lower affinity for C type lectins and fewer N linked glycosylation sites. To enhance these studies we worked closely with programmers and bioinformatic specialists to develop robust NGS analysis pipelines to determine transmission fitness from multivirus competitions and more recently, we optimized EIS-MS techniques to analyze gp120 glycans. We have proposed four highly inter-related aims to test our hypotheses: Specific Aim 1. In vivo analyses of HIV-1 in endocervical (EnC) and plasma samples and determinants of new HIV transmissions. Examine Env sequence features in the EnC and blood of newly infected women as well as in women with HIV-1 infection in the EnC but who have not seroconverted. Specific Aim 2. Characterizing the properties of transmitted/founder (TF) HIV variant in blood versus the transmitted HIV-1 population in the female and male genital tract: Ex vivo study. Measure trapped replication in the tissue versus transmission in human penile, foreskin, cervical, and vaginal explant model. Specific Aim 3. To measure lectin binding affinity and to analyze the glycosylation pattern on the gp120 Env of highly transmissible TF HIV-1 using new gp120 purification techniques and EIS-MS. Specific Aim 4. To modify the glycans on TF and EnC viruses and to determine optimal HIV Env for male to female HIV transmissions using the same methods described in aims 2 and 3.


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 = $411,631 )
2024	2024	UNIVERSITY OF WESTERN ONTARIO	1393 WESTERN ROAD	LONDON	ON			CAN	Allergy and Infectious Diseases Research	000	18	4/26/2024	NON-COMPETING CONTINUATION	$411,631
														Subtotal = $411,631

Issue Date FY: 2023 ( Subtotal = $411,631 )
2023	2023	UNIVERSITY OF WESTERN ONTARIO	1393 WESTERN ROAD	LONDON	ON			CAN	Allergy and Infectious Diseases Research	000	17	4/26/2023	NON-COMPETING CONTINUATION	$411,631
														Subtotal = $411,631

Issue Date FY: 2022 ( Subtotal = $411,631 )
2022	2022	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON			CAN	Allergy and Infectious Diseases Research	000	16	4/27/2022	NON-COMPETING CONTINUATION	$411,631
														Subtotal = $411,631

Issue Date FY: 2021 ( Subtotal = $411,631 )
2021	2021	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON			CAN	Allergy and Infectious Diseases Research	001	15	5/14/2021	NON-COMPETING CONTINUATION	$411,631
2021	2020	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON			CAN	Allergy and Infectious Diseases Research	000	14	4/14/2021	COMPETING CONTINUATION	$0
														Subtotal = $411,631

Issue Date FY: 2020 ( Subtotal = $411,631 )
2020	2020	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON	N6A 5B8		CAN	Allergy and Infectious Diseases Research	000	14	5/11/2020	COMPETING CONTINUATION	$411,631
														Subtotal = $411,631

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON	N6A 5B8		CAN	Allergy and Infectious Diseases Research	000	13	8/18/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $343,027 )
2016	2016	UNIVERSITY OF WESTERN ONTARIO	RESEARCH DEVELOPMENT & SVCS	LONDON, ONTARIO				CAN	Allergy and Infectious Diseases Research	000	13	7/25/2016	NON-COMPETING CONTINUATION	$343,027
														Subtotal = $343,027

Issue Date FY: 2015 ( Subtotal = $348,987 )
2015	2015	UNIVERSITY OF WESTERN ONTARIO	RESEARCH DEVELOPMENT & SVCS	LONDON, ONTARIO				CAN	Allergy and Infectious Diseases Research	000	12	8/10/2015	NON-COMPETING CONTINUATION	$348,987
														Subtotal = $348,987

Issue Date FY: 2014 ( Subtotal = $347,410 )
2014	2014	UNIVERSITY OF WESTERN ONTARIO	RESEARCH DEVELOPMENT & SVCS	LONDON, ONTARIO				CAN	Allergy and Infectious Diseases Research	000	11	8/29/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$347,410
														Subtotal = $347,410

Issue Date FY: 2013 ( Subtotal = $449,769 )
2013	2013	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	10	7/30/2013	COMPETING CONTINUATION	$449,769
														Subtotal = $449,769

Issue Date FY: 2011 ( Subtotal = $371,372 )
2011	2011	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	9	8/15/2011	NON-COMPETING CONTINUATION	$371,372
														Subtotal = $371,372

Issue Date FY: 2010 ( Subtotal = $556,640 )
2010	2010	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	7	4/19/2010	SUPPLEMENT FOR EXPANSION	$14,250
2010	2010	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	002	8	7/23/2010	NON-COMPETING CONTINUATION	$470,819
2010	2010	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	7	3/26/2010	SUPPLEMENT FOR EXPANSION	$71,571
														Subtotal = $556,640

Issue Date FY: 2009 ( Subtotal = $378,911 )
2009	2009	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	7	8/21/2009	NON-COMPETING CONTINUATION	$378,911
														Subtotal = $378,911

Issue Date FY: 2008 ( Subtotal = $378,911 )
2008	2008	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	6	8/22/2008	NON-COMPETING CONTINUATION	$378,911
														Subtotal = $378,911

Issue Date FY: 2007 ( Subtotal = $386,250 )
2007	2007	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	5	8/14/2007	COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2005 ( Subtotal = $293,959 )
2005	2005	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Microbiology and Infectious Diseases Research	000	4	8/23/2005	NON-COMPETING CONTINUATION	$293,959
														Subtotal = $293,959

Issue Date FY: 2004 ( Subtotal = $294,310 )
2004	2004	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Microbiology and Infectious Diseases Research	000	3	9/4/2004	NON-COMPETING CONTINUATION	$294,310
														Subtotal = $294,310

Issue Date FY: 2003 ( Subtotal = $296,882 )
2003	2003	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Microbiology and Infectious Diseases Research	000	2	9/19/2003	NON-COMPETING CONTINUATION	$296,882
														Subtotal = $296,882

Issue Date FY: 2002 ( Subtotal = $296,460 )
2002	2002	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Microbiology and Infectious Diseases Research	000	1	9/18/2002	NEW	$296,460
														Subtotal = $296,460

Grand Total All Awards = $6,801,043

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Determinants of HIV transmission fitness

Award Number: R01AI049170

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: 09/27/2002

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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