Saturday, September 13, 2025 9/13/2025

GAG AND CYCLOPHILIN IN HIV-1 REPLICATION

Award Number: R01AI036199
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: 08/01/1994
PERIOD OF PERFORMANCE END DATE: 12/31/2009

Group Awards By:

View Award Description

GAG AND CYCLOPHILIN IN HIV-1 REPLICATION - DESCRIPTION (provided by applicant): Efforts to discover new anti-HIV-1 therapies and to elicit effective anti-HIV-1 immunity have increasingly focused on human factors that regulate HIV-1 replication and pathogenesis. Cyclophilin A, a peptidyl-prolyl isomerase that regulates protein-folding and is itself a receptor for the immunosuppressive drug cyclosporine, binds HIV-1 Gag via the CA domain. The interaction stimulates HIV-1 reverse transcription in human cells but inhibits it in owl monkey (OMK) or macaque cells. These phenotypes appear to result from effects of cyclophilin A on HIV-1 CA accessibility to species-specific Lvl/Refl host restriction factors. Also, via a novel conformational switch, cyclophilin A inhibits the Itk tyrosine kinase, suggesting that Gag binding to cyclophilin A might contribute to HIV-1 pathogenesis by disrupting CD4 v T cell effector function. These and other observations made since the discovery of the Gag/cyclophilin A interaction in 1993 serve as the basis for current specific aims. Aim 1. Several complementary approaches will be used to clone OMK Lvl and human Refl, including a functional screen of a cDNA library from owl monkey cells, a modified two-hybrid screen using a CA-fusion bait that saturates OMK restriction, and subtraction libraries from cell line subclones selected for loss of restriction. Aim 2. As203, m-Cl-CCP, and PKl1195 all disrupt mitochondrial membrane potential and decrease Refl restriction. Select primate species will be challenged to determine if the drugs also inhibit Lvl. Preliminary data suggest that cyclophilin A protects HIV-1 from Refl; to test this hypothesis the effect of the drugs on HIV-1 infectivity will be examined in contexts where cyclophilin A or Refl are disrupted. Detailed biochemical and cell biological effects of the drugs will be characterized and contrasted with those of cyclosporine. Aim 3. Under pressure from cyclosporine, HIV-1 acquires mutations in sequences encoding a type II turn in CA that are sufficient to confer cyclosporine-resistance. In certain human cell lines, these mutants replicate poorly and are cyclosporine-dependent. Evidence that this is due to a new restriction activity present in certain individuals will be sought. Group O viruses have alterations in the same gag sequences, are cyclosporine-resistant, and will be examined for sensitivity to the same activity. Aim 4. It will be determined if HIV-1 Gag disrupts the cyclophilin A-Itk interaction and causes elevated Th2 cytokine and IL-2 expression from effector/memory CD4* T cells as is seen in cyclophilin A knockout mice. These immunologic abnormalities would be expected to contribute to HIV-1 replication and pathogenesis.


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: 2009 ( Subtotal = $0 )
2009	2008	UNIVERSITY OF GENEVA SCHOOL OF MEDICINE	1 RUE MICHEL-SERVET	GENEVA		00000		CHE	Allergy and Infectious Diseases Research	000	15	6/5/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2007 ( Subtotal = $204,807 )
2007	2007	INSTITUTE FOR RESEARCH IN BIOMEDICINE	Research Administration 630 West 168th Street, Box 49	NEW YORK	NY	100323725	NEW YORK	USA	Allergy and Infectious Diseases Research	000	14	8/17/2007	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$204,807
														Subtotal = $204,807

Issue Date FY: 2006 ( Subtotal = $313,491 )
2006	2006	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Allergy and Infectious Diseases Research	000	13	8/4/2006	NON-COMPETING CONTINUATION	$313,491
														Subtotal = $313,491

Issue Date FY: 2005 ( Subtotal = $320,605 )
2005	2005	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Microbiology and Infectious Diseases Research	000	12	7/18/2005	NON-COMPETING CONTINUATION	$320,605
														Subtotal = $320,605

Issue Date FY: 2004 ( Subtotal = $320,192 )
2004	2004	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Microbiology and Infectious Diseases Research	000	11	6/18/2004	COMPETING CONTINUATION	$320,192
														Subtotal = $320,192

Issue Date FY: 2003 ( Subtotal = $396,478 )
2003	2003	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Microbiology and Infectious Diseases Research	000	10		NON-COMPETING CONTINUATION	$396,478
														Subtotal = $396,478

Issue Date FY: 2002 ( Subtotal = $388,042 )
2002	2002	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Microbiology and Infectious Diseases Research	000	9	4/29/2002	NON-COMPETING CONTINUATION	$388,042
														Subtotal = $388,042

Issue Date FY: 2001 ( Subtotal = $379,848 )
2001	2001	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Microbiology and Infectious Diseases Research	000	8	4/12/2001	NON-COMPETING CONTINUATION	$379,848
														Subtotal = $379,848

Issue Date FY: 2000 ( Subtotal = $371,895 )
2000	2000	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Microbiology and Infectious Diseases Research	000	7	3/22/2000	NON-COMPETING CONTINUATION	$371,895
														Subtotal = $371,895

Issue Date FY: 1999 ( Subtotal = $368,073 )
1999	1999	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Microbiology and Infectious Diseases Research	000	6	2/18/1999	COMPETING CONTINUATION	$368,073
														Subtotal = $368,073

Issue Date FY: 1998 ( Subtotal = $323,324 )
1998	1998	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Microbiology and Infectious Diseases Research	000	5	4/30/1998	NON-COMPETING CONTINUATION	$323,324
														Subtotal = $323,324

Grand Total All Awards = $3,386,755

Top

All Categories

About

Search

Reports

Data Submission

Award Information

GAG AND CYCLOPHILIN IN HIV-1 REPLICATION

Award Number: R01AI036199

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: 08/01/1994

PERIOD OF PERFORMANCE END DATE: 12/31/2009

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer