Friday, October 31, 2025 10/31/2025

Immunoregulatory networks and HIV pathogenesis

Award Number: R01HL092565
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2018

Group Awards By:

View Award Description

Immunoregulatory networks and HIV pathogenesis - DESCRIPTION (provided by applicant): Combination antiretroviral therapy (ART) has resulted in a major decrease in morbidity and mortality in HIV- infection. However, ART does not eradicate virus or restore HIV-specific immune responses capable of controlling viral replication once therapy is interrupted. Development of interventions that could generate immune responses capable of maintaining HIV suppression after cessation of ART and improve efficacy of vaccine candidates would be a crucial clinical advance. Evidence suggests that effective HIV-specific CD4 T cells will be required to achieve this goal, yet these cells remain seriously understudied. The lack of restoration of effective HIV-specific CD4 T helper responses in spite of extended ART raised the possibility that these responses are irreversibly crippled. However, the results we have generated during the first four years of this grant support a striking conclusion: that CD4 T cell impairment in HIV-infection is to a significant extent under control of inhibitory mechanisms that can be reverted by manipulation of regulatory networks. Data suggest that one of these pathways, PD-1, also plays an important role in the maintenance of HIV reservoirs, making it a very attractive therapeutic target. In this competing renewal we propose to build on the major progress made during the initial funding period and to utilize combined approaches of cellular biology, molecular immunology and advanced cell imaging to pinpoint critical events that regulate effective and inefficient HIV-specific CD4 T cell responses. We also propose to investigate another neglected area of HIV-research: the impact that ineffective HIV-specific CD4 T cell responses have on antigen-presenting cell functions. In Aim 1, we will identify critical gene signatures of functional and exhausted HIV-specific CD4 T cells. We will determine the master transcription factors that are regulated by PD-1 in HIV-specific CD4 T cells and define their role in the control of exhausted CD4 T cell functions. We will examine the potential for HIV-specific CD4 T cell functional plasticity by overexpressing or silencing these master genes in primary cells. In Aim 2 we will use advanced live imaging to determine the dynamics of immunological synapses built by functional and exhausted HIV- specific CD4 T cells. We will define the role of individual co-inhibitors and determine whether optimized co- stimulatory signaling can prevent this defective synapse formation and function. In Aim 3 we will define specific defects in licensing of antigen-presenting cells by HIV-specific CD4 T cells, and specific mechanisms of APC impairment. We will determine whether APC present inappropriate responses to stimulatory signals. By selectively blocking molecules expressed by dysfunctional CD4 T cells, we will determine events causally involved in the perturbation of APC functions. We will also define how the interplay between regulatory pathways leads to the observed defects. This proposal will provide novel understanding of the molecular basis for functional differences between protective and ineffective HIV-specific CD4 T cells and will identify new therapeutic targets to generate effective HIV-specific immunity in ART-treated and uninfected persons.


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: 2019 ( Subtotal = $0 )
2019	2015	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Blood Diseases and Resources Research	001	9	9/30/2019	NON-COMPETING CONTINUATION	$0
2019	2014	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Blood Diseases and Resources Research	000	8	8/29/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	3840 RUE SAINT-URBAIN	MONTREAL	PQ	H2W 1T8		CAN	Blood Diseases and Resources Research	000	9	6/29/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $265,950 )
2015	2015	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Blood Diseases and Resources Research	000	9	5/13/2015	NON-COMPETING CONTINUATION	$265,950
														Subtotal = $265,950

Issue Date FY: 2014 ( Subtotal = $264,600 )
2014	2014	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Blood Diseases and Resources Research	000	8	7/22/2014	NON-COMPETING CONTINUATION	$264,600
														Subtotal = $264,600

Issue Date FY: 2013 ( Subtotal = $257,040 )
2013	2013	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Blood Diseases and Resources Research	001	7	8/5/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$257,040
2013	2012	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Blood Diseases and Resources Research	000	6	8/1/2013	COMPETING CONTINUATION	$0
														Subtotal = $257,040

Issue Date FY: 2012 ( Subtotal = $435,209 )
2012	2012	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Blood Diseases and Resources Research	000	6	7/23/2012	COMPETING CONTINUATION	$435,209
2012	2012	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Blood Diseases and Resources Research	001	6	8/6/2012	COMPETING CONTINUATION	$0
														Subtotal = $435,209

Issue Date FY: 2011 ( Subtotal = $436,700 )
2011	2011	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Blood Diseases and Resources Research	000	5	8/8/2011	NON-COMPETING CONTINUATION	$436,700
														Subtotal = $436,700

Issue Date FY: 2010 ( Subtotal = $436,700 )
2010	2010	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Blood Diseases and Resources Research	000	4	7/19/2010	NON-COMPETING CONTINUATION	$436,700
														Subtotal = $436,700

Issue Date FY: 2009 ( Subtotal = $436,700 )
2009	2009	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Blood Diseases and Resources Research	000	3	8/27/2009	NON-COMPETING CONTINUATION	$436,700
														Subtotal = $436,700

Issue Date FY: 2008 ( Subtotal = $446,075 )
2008	2008	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	9/5/2008	NON-COMPETING CONTINUATION	$446,075
														Subtotal = $446,075

Issue Date FY: 2007 ( Subtotal = $446,075 )
2007	2007	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Blood Diseases and Resources Research	000	1	8/27/2007	NEW	$446,075
														Subtotal = $446,075

Grand Total All Awards = $3,425,049

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Immunoregulatory networks and HIV pathogenesis

Award Number: R01HL092565

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2018

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer