Abstract

proposal) Macrophages play a key role in the pathogenesis of HIV infection, in that they serve as a main reservoir of persistent viral replication throughout the infection. However, the mechanisms regulating viral persistence remain uncharacterized. The NF-kB/rel family of transcription factors is essential for HIV transcription and replication in macrophages. NF-kB activity is constitutive in the nuclei of macrophages, in the form of RelB, and exists as a cytosolic and inducible pool of NF-kB (p50/65) associated with IkB. Studies from this lab have identified components of NF-kB that are unique to macrophages, this includes the targeting of IkBa and nuclear translocation of NF-kB following HIV infection. This process is regulated by induced kinases that phosphorylate IkBa at S32/36. These workers have identified an inducible IkBa kinase in macrophages, casein kinase II (PK-CK2). The primary goal of the proposal is to characterize the molecular mechanisms whereby NF-kB participates in the regulation of HIV persistence in human macrophages.
The aims are: 1) to characterize the molecular composition and regulation of constitutive NF-kB (RelB) activity and its relevance to virus replication; 2) to study the mechanisms of HIV-dependent activation of the induced pool of NF-kB through IkBa targeting; and 3) to characterize the function of the inducible IkBa kinase and the relationship to PK-CK2.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036076-08
Application #
6373394
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Wassef, Nabila M
Project Start
1994-08-01
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2003-07-31
Support Year
8
Fiscal Year
2001
Total Cost
$231,135
Indirect Cost

  Institution

Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905

  Publications

Trushin, Sergey A; Pennington, Kevin N; Carmona, Eva M et al. (2003) Protein kinase Calpha (PKCalpha) acts upstream of PKCtheta to activate IkappaB kinase and NF-kappaB in T lymphocytes. Mol Cell Biol 23:7068-81
Solan, Nancie J; Miyoshi, Hiroko; Carmona, Eva M et al. (2002) RelB cellular regulation and transcriptional activity are regulated by p100. J Biol Chem 277:1405-18
Bren, G D; Solan, N J; Miyoshi, H et al. (2001) Transcription of the RelB gene is regulated by NF-kappaB. Oncogene 20:7722-33
Asin, S; Bren, G D; Carmona, E M et al. (2001) NF-kappaB cis-acting motifs of the human immunodeficiency virus (HIV) long terminal repeat regulate HIV transcription in human macrophages. J Virol 75:11408-16
Trushin, S A; Pennington, K N; Algeciras-Schimnich, A et al. (1999) Protein kinase C and calcineurin synergize to activate IkappaB kinase and NF-kappaB in T lymphocytes. J Biol Chem 274:22923-31
McElhinny, J A; Trushin, S A; Bren, G D et al. (1996) Casein kinase II phosphorylates I kappa B alpha at S-283, S-289, S-293, and T-291 and is required for its degradation. Mol Cell Biol 16:899-906
Folgueira, L; Algeciras, A; MacMorran, W S et al. (1996) The Ras-Raf pathway is activated in human immunodeficiency virus-infected monocytes and particpates in the activation of NF-kappa B. J Virol 70:2332-8
McElhinny, J A; MacMorran, W S; Bren, G D et al. (1995) Regulation of I kappa B alpha and p105 in monocytes and macrophages persistently infected with human immunodeficiency virus. J Virol 69:1500-9
Herrero, J A; Mathew, P; Paya, C V (1995) LMP-1 activates NF-kappa B by targeting the inhibitory molecule I kappa B alpha. J Virol 69:2168-74
Steffan, N M; Bren, G D; Frantz, B et al. (1995) Regulation of IkB alpha phosphorylation by PKC- and Ca(2+)-dependent signal transduction pathways. J Immunol 155:4685-91