: The global AIDS epidemic continues to rage, with 40 million people infected with HIV-1 or debilitated by AIDS. Analysis of HIV-1 infected individuals and studies in animal models show the rapid onset of AIDS requires expression of the HIV-1 protein Nef. This lentivirus protein has manifold roles in the pathophysiology of AIDS, including the downregulation of the host CD4 and MHC-1 molecules in infected cells. The downregulation of CD4 eliminates interference of the viral receptor with HIV-1 envelopment and MHC-1 downregulation enables the virus to evade the immune surveillance system. Despite the importance of Nef-mediated downregulation of MHC-1 to the development of AIDS, little is known regarding the cellular and biochemical pathways that control this process. Recently, this laboratory reported the identification of the cellular protein, PACS-1, that they believe controls the Nef-mediated downregulation of MHC-1. They showed PACS-1 binds to HIV-1 Nef to form a protein complex in cells. Moreover, HIV-1 Nef requires PACS-1 to specifically downregulate MHC-1 by redistributing this immune surveillance molecule to the trans-Golgi network. The identification of the PACS-1/Nef complex has provided some of the first insights into the mechanism of HIV-1-mediated downregulation of MHC-1 molecules. The proposed studies first will identify the structural determinants required for the association of HIV-1 Nef and PACS-1 and elucidate how formation of the PACS-1/Nef complex is regulated. Second, they will identify the cellular pathway used by PACS-1/Nef to sequester MHC-1 in the trans-Golgi network. Third, they will test the possibility that the PACS-1/Nef complex is a potential pharmacological target for disrupting HIV-1 immune evasion. Together, these studies will increase our knowledge of the biochemical and cellular basis of HIV-1's ability to evade the immune surveillance system, as well as provide new insights into pharmacological strategies to block this process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049793-02
Application #
6511576
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Voulgaropoulou, Frosso
Project Start
2001-04-01
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$338,730
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Dikeakos, Jimmy D; Thomas, Laurel; Kwon, Grace et al. (2012) An interdomain binding site on HIV-1 Nef interacts with PACS-1 and PACS-2 on endosomes to down-regulate MHC-I. Mol Biol Cell 23:2184-97
Aslan, Joseph E; You, Huihong; Williamson, Danielle M et al. (2009) Akt and 14-3-3 control a PACS-2 homeostatic switch that integrates membrane traffic with TRAIL-induced apoptosis. Mol Cell 34:497-509
Youker, Robert T; Shinde, Ujwal; Day, Robert et al. (2009) At the crossroads of homoeostasis and disease: roles of the PACS proteins in membrane traffic and apoptosis. Biochem J 421:1-15
Jenkins, Paul M; Zhang, Lian; Thomas, Gary et al. (2009) PACS-1 mediates phosphorylation-dependent ciliary trafficking of the cyclic-nucleotide-gated channel in olfactory sensory neurons. J Neurosci 29:10541-51
Aslan, Joseph E; Thomas, Gary (2009) Death by committee: organellar trafficking and communication in apoptosis. Traffic 10:1390-404
Myhill, Nathan; Lynes, Emily M; Nanji, Jalal A et al. (2008) The subcellular distribution of calnexin is mediated by PACS-2. Mol Biol Cell 19:2777-88
Atkins, Katelyn M; Thomas, Laurel; Youker, Robert T et al. (2008) HIV-1 Nef binds PACS-2 to assemble a multikinase cascade that triggers major histocompatibility complex class I (MHC-I) down-regulation: analysis using short interfering RNA and knock-out mice. J Biol Chem 283:11772-84
Hung, Chien-Hui; Thomas, Laurel; Ruby, Carl E et al. (2007) HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I. Cell Host Microbe 1:121-33
Bouard, David; Sandrin, Virginie; Boson, Bertrand et al. (2007) An acidic cluster of the cytoplasmic tail of the RD114 virus glycoprotein controls assembly of retroviral envelopes. Traffic 8:835-47
Mansouri, Mandana; Douglas, Janet; Rose, Patrick P et al. (2006) Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells. Blood 108:1932-40

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