Abstract

(abbreviated from the applicant's page 2) The cellular protein cyclophilin A (CyPA) binds to a proline-rich loop in the CA domain of HIV-1 Gag and is thereby incorporated into virions, where it promotes an early event in the infectious cycle. Inhibitors of the Gag- CyPA interaction disrupt CyPA packaging and attenuate infectivity. The goal of this proposal is to develop a detailed understanding of CyPA function in HIV-1 replication. The four specific aims are: (1) To use human T cells lines engineered to lack functional genes for CyPA, in order to study the ability of HIV-1 to replicate in absence of CyPA, and to test to what extent other cyclophilins can substitute for CyPA. (2) To determine if it is the peptidyl prolyl isomerase (PPIase) activity of CyPA that is the key feature of this protein that performs a function important for the HIV-1 life cycle, or alternatively if it is the CA- binding activity itself. (3) To pinpoint the sequences that determine CyPA dependence in HIV-1, making use of mutants and rare HIV-1 isolates do not need CyPA, even though they incorporate it into virions. (4) To gain biochemical evidence for the function of CyPA for HIV-1 replication, including a test of the hypothesis that this cellular protein acts by destabilizing HIV-1 cores, thereby promoting disassembly in the newly infected cell.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036199-07
Application #
6169996
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Bridges, Sandra H
Project Start
1994-08-01
Project End
2004-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
7
Fiscal Year
2000
Total Cost
$371,895
Indirect Cost

  Institution

Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032

  Publications

Sokolskaja, Elena; Olivari, Silvia; Zufferey, Madeleine et al. (2010) Cyclosporine blocks incorporation of HIV-1 envelope glycoprotein into virions. J Virol 84:4851-5
Mangeat, Bastien; Gers-Huber, Gustavo; Lehmann, Martin et al. (2009) HIV-1 Vpu neutralizes the antiviral factor Tetherin/BST-2 by binding it and directing its beta-TrCP2-dependent degradation. PLoS Pathog 5:e1000574
Sebastian, Sarah; Grutter, Christian; Strambio de Castillia, Caterina et al. (2009) An invariant surface patch on the TRIM5alpha PRYSPRY domain is required for retroviral restriction but dispensable for capsid binding. J Virol 83:3365-73
Strebel, Klaus; Luban, Jeremy; Jeang, Kuan-Teh (2009) Human cellular restriction factors that target HIV-1 replication. BMC Med 7:48
Neagu, Martha R; Ziegler, Patrick; Pertel, Thomas et al. (2009) Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components. J Clin Invest 119:3035-47
Kaul, Artur; Stauffer, Sarah; Berger, Carola et al. (2009) Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics. PLoS Pathog 5:e1000546
Santoni de Sio, Francesca Romana; Gritti, Angela; Cascio, Paolo et al. (2008) Lentiviral vector gene transfer is limited by the proteasome at postentry steps in various types of stem cells. Stem Cells 26:2142-52
Goujon, Caroline; Arfi, Vanessa; Pertel, Thomas et al. (2008) Characterization of simian immunodeficiency virus SIVSM/human immunodeficiency virus type 2 Vpx function in human myeloid cells. J Virol 82:12335-45
Berthoux, Lionel; Sebastian, Sarah; Muesing, Mark A et al. (2007) The role of lysine 186 in HIV-1 integrase multimerization. Virology 364:227-36
Takeuchi, Hiroaki; Buckler-White, Alicia; Goila-Gaur, Ritu et al. (2007) Vif counteracts a cyclophilin A-imposed inhibition of simian immunodeficiency viruses in human cells. J Virol 81:8080-90

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