Abstract

The ability of the human immunodeficiency virus (HIV) to escape immune surveillance in vivo is central to its pathogenicity and potentially limits our ability to develop effective vaccines. In HIV+ individuals, anti-HIV cytolytic T lymphocytes (CTLs) are clearly abundant and play a role in limiting viral loads, but they are unable to eradicate the virus. To better understand this enigma, we studied the efficacy with which anti-HIV CTLs are able to kill infected cells. This required the development of a unique system in which all infected cells could be identified (and quantitated) by the expression of placental alkaline phosphatase (FLAP). We used the PLAP marker to monitor the outcome of infected cells treated with CTLs. We found that HIV encodes at least one factor (nef) that protects infected cells from CTLs. Nef limited the ability of CTLs to kill infected cells by decreasing the density of MHC class I-epitope complexes on the surface of infected cells. In this proposal, we present experiments that will shed more light on the molecular mechanism of nef-mediated MHC class I downmodulation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046998-03
Application #
6511217
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (01))
Program Officer
Wassef, Nabila M
Project Start
2000-04-15
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
3
Fiscal Year
2002
Total Cost
$296,759
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
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