Abstract

HIV-1Nef is a 27-34 kDa myristoylated protein that has multiple activities defined in vitro. These include: alterations in signaling with disruption of pro-apoptotic pathways; increased viral infectivity; T cell activation; CD28, CD4 and MHC-I downmodulation and protection of infected primary T cells form CTL lysis. Based on in vivo studies, it is known that an intact nef gene is necessary for the timely development of AIDS, and in infected monkeys, the ability of Nef to downmodulate MHC-I is an important component of Nef's in vivo activities. The mechanism used by Nef to downmodulate MHC-I remains unknown. Our data indicates that, in T cells, Nef binds the MHC-I cytoplasmic tail, prevents it from being phosphorylated and disrupts MHC-I transport from the trans-Golgi network to the plasma membrane. Studies are proposed to better understand the detailed molecular mechanism of MHC-I downmodulation. These studies should aid in the development of inhibitors that disrupt HIV immune evasion.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046998-09
Application #
7390407
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
1999-12-01
Project End
2009-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
9
Fiscal Year
2008
Total Cost
$316,183
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Collins, David R; Lubow, Jay; Lukic, Zana et al. (2015) Vpr Promotes Macrophage-Dependent HIV-1 Infection of CD4+ T Lymphocytes. PLoS Pathog 11:e1005054
Mashiba, Michael; Collins, David R; Terry, Valeri H et al. (2014) Vpr overcomes macrophage-specific restriction of HIV-1 Env expression and virion production. Cell Host Microbe 16:722-35
Kulpa, Deanna A; Del Cid, Natasha; Peterson, Kirsten A et al. (2013) Adaptor protein 1 promotes cross-presentation through the same tyrosine signal in major histocompatibility complex class I as that targeted by HIV-1. J Virol 87:8085-98
Heigele, Anke; Schindler, Michael; Gnanadurai, Clement W et al. (2012) Down-modulation of CD8?? is a fundamental activity of primate lentiviral Nef proteins. J Virol 86:36-48
Wonderlich, Elizabeth R; Leonard, Jolie A; Kulpa, Deanna A et al. (2011) ADP ribosylation factor 1 activity is required to recruit AP-1 to the major histocompatibility complex class I (MHC-I) cytoplasmic tail and disrupt MHC-I trafficking in HIV-1-infected primary T cells. J Virol 85:12216-26
Wonderlich, Elizabeth R; Leonard, Jolie A; Collins, Kathleen L (2011) HIV immune evasion disruption of antigen presentation by the HIV Nef protein. Adv Virus Res 80:103-27
Schaefer, Malinda R; Williams, Maya; Kulpa, Deanna A et al. (2008) A novel trafficking signal within the HLA-C cytoplasmic tail allows regulated expression upon differentiation of macrophages. J Immunol 180:7804-17
Schaefer, Malinda R; Wonderlich, Elizabeth R; Roeth, Jeremiah F et al. (2008) HIV-1 Nef targets MHC-I and CD4 for degradation via a final common beta-COP-dependent pathway in T cells. PLoS Pathog 4:e1000131
Wonderlich, Elizabeth R; Williams, Maya; Collins, Kathleen L (2008) The tyrosine binding pocket in the adaptor protein 1 (AP-1) mu1 subunit is necessary for Nef to recruit AP-1 to the major histocompatibility complex class I cytoplasmic tail. J Biol Chem 283:3011-22
Roeth, Jeremiah F; Collins, Kathleen L (2006) Human immunodeficiency virus type 1 Nef: adapting to intracellular trafficking pathways. Microbiol Mol Biol Rev 70:548-63

Showing the most recent 10 out of 17 publications