Cyclophilin A (CypA), a cellular protein which catalyzes the cis-trans isomerization of peptidyl-prolyl bonds, is incorporated at high abundance in each virion of the type I human immunodeficiency virus (HIV-1). CypA packaging is required for viral replication, possibly because the protein helps to uncoat the capsid shell of the virus upon infection. CypA packaging occurs by direct binding with the HIV-1 capsid protein (CA); this event occurs early in virion particle assembly. Sundquist et al. have determined that the primary CypA binding site on the HIV-1 capsid protein resides within the capsid hexapeptide 219 His-Ala-Gly-Pro-Ile-Ala 224. In addition, Sundquist et al. have solved the x-ray structure of the CypA/hexapeptide complex, providing the first structural details of CypA/CA interactions. However, further experiments are required to determine the thermodynamic basis for CypA binding and to assess the functional consequences of this essential interaction. The proposed research has three specific aims, designed to reveal how and why the HIV-1 virus packages CypA: I) Structural characterization of the CypA/HAGPIA complex in solution, II) Determine thermodynamic contribution for CypA binding to intact and sub-portions of the HIV-1 CA, and III) Investigate high binding affinity peptides to CypA. This research will reveal the biochemistry and solution structure of the CypA/CA interaction and may reveal the role of cyclophilin A in HIV-1 replication. In addition, this research will provide energetic and structural details necessary for the rational design of therapeutic compounds that disrupt the CypA/CA interaction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI009708-03
Application #
2671631
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1998-07-15
Project End
Budget Start
1998-07-15
Budget End
1999-07-14
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112