Aberrant expression of inflammatory cytokines during the HIV-1 infection has been implicated in the pathogenesis of AIDS. However, the molecular mechanism by which HIV-1 modulates the expression of cytokine genes has not completely been clarified. They have recently shown (Popik & Pitha, 1996) that binding of HIV-1 virions or gp 120 to the CD4 receptors on T-cells results in the association of Lck (which is associated with CD4 receptor) with Raf-1 kinase which leads to Raf-1 activation. The activation depends on the presence of functioning CD4 receptors and is not Ras-mediated. They have further demonstrated (see preliminary results) that this novel signaling pathway is functional and results in the activation of several nuclear transcription factors (AP-1, NF-kB, C/EBP) with the consequent activation of transcription of several cytokine and chemokine genes as well as Fas ligand. Although we have unambiguously demonstrated that this pathway is mediated by the CD4 receptors, the question arises whether the binding of HIV-1 virions to the newly described HIV-1 coreceptor, CXCR4 participates or contributes to this signaling. Since the syncytium-inducing viruses that emerge in the later stages of HIV-1 infection use CXCR4 as coreceptor, it is likely that binding of these viruses to this coreceptor induces intracellular signaling, contributing to the activation of inflammatory genes and to the rapid decline of CD4+ T-cells. The studies proposed are designed to characterize and analyze the unique signaling pathway activated by HIV-1 binding to the CXCR4 receptor.
In Aim #1, they will analyze the CXCR4-mediated expression of inflammatory genes and induction of nuclear transcription of nuclear transcription factors after binding of HIV-1.
In Aim #2, they will investigate the role of CXCR4 signaling in the infection of peripheral blood CD4+ naive and memory T lymphocytes.
In Aim #3, they plan to identify CXCR4 sequences involved in HIV-1 mediated signaling. Finally, in Aim #4, they will investigate the molecular mechanism of SDF-1 inhibition of HIV-1 induced signaling. They believe that this study will contribute to our better understanding of HIV-1-induced pathogenicity and will provide a rational basis for new approaches to inhibit HIV replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042557-02
Application #
2856098
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Program Officer
Plaeger, Susan F
Project Start
1998-01-01
Project End
2001-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Fiala, Milan; Eshleman, Amy J; Cashman, John et al. (2005) Cocaine increases human immunodeficiency virus type 1 neuroinvasion through remodeling brain microvascular endothelial cells. J Neurovirol 11:281-91
Liu, Nancy Q; Lossinsky, Albert S; Popik, Waldemar et al. (2002) Human immunodeficiency virus type 1 enters brain microvascular endothelia by macropinocytosis dependent on lipid rafts and the mitogen-activated protein kinase signaling pathway. J Virol 76:6689-700
Popik, Waldemar; Alce, Timothy M; Au, Wei-Chun (2002) Human immunodeficiency virus type 1 uses lipid raft-colocalized CD4 and chemokine receptors for productive entry into CD4(+) T cells. J Virol 76:4709-22
Twu, Cheryl; Liu, Nancy Q; Popik, Waldemar et al. (2002) Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways. Proc Natl Acad Sci U S A 99:14386-91
Popik, W; Pitha, P M (2000) Inhibition of CD3/CD28-mediated activation of the MEK/ERK signaling pathway represses replication of X4 but not R5 human immunodeficiency virus type 1 in peripheral blood CD4(+) T lymphocytes. J Virol 74:2558-66
Popik, W; Hesselgesser, J E; Pitha, P M (1998) Binding of human immunodeficiency virus type 1 to CD4 and CXCR4 receptors differentially regulates expression of inflammatory genes and activates the MEK/ERK signaling pathway. J Virol 72:6406-13
Popik, W; Pitha, P M (1998) Early activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in response to binding of simian immunodeficiency virus to Jurkat T cells expressing CCR5 Virology 252:210-7
Fons, M; Nokta, M; Cerruti-Sola, S et al. (1991) Amiloride inhibition of human cytomegalovirus replication. Proc Soc Exp Biol Med 196:89-96
Albrecht, T; Boldogh, I; Fons, M et al. (1989) Cell-activation responses to cytomegalovirus infection relationship to the phasing of CMV replication and to the induction of cellular damage. Subcell Biochem 15:157-202
AbuBakar, S; Au, W W; Legator, M S et al. (1988) Induction of chromosome aberrations and mitotic arrest by cytomegalovirus in human cells. Environ Mol Mutagen 12:409-20

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