We have recently shown that when monocyte-derived macrophages (MDM) are exposed to HIV-1, they produce large amounts of two C-X-C chemokines: Interleukin 8 (IL-8) and Growth-Regulated Oncogene alpha (GRO-alpha). This stimulation appears to be mediated by a pathway involving a tyrosine kinase, PKC-zeta, and perhaps NF-kappaB. IL-8 and GRO-alpha then, in turn, feed back and stimulate HIV-1 replication in both MDM and lymphocytes, likely by increasing viral entry. By blocking these chemokines or their receptors, CXCR1and/or CXCR2, we can inhibit HTV-1 replication. Companies have already developed agents that block the function of the above chemokines in order to treat inflammatory diseases, and we have demonstrated that a small molecule inhibitor of CXCR2 is able to inhibit HIV-1 replication. We now propose to examine the magnitude to which diverse clinical isolates of HIV stimulate the production of GRO-alpha and EL-8. The effect of IL-8 and GRO-alpha on the replication of a range of HIV isolates will also be assessed. These experiments will clarify how broadly applicable, and hence clinically important, these autocrine/paracrine loops involving chemokine, receptor, and HIV are. We will further test the hypothesis that HIV stimulates PKC-zeta and hence NF-kappaB, leading to increased transcription and production of IL-8 and GRO-alpha, which in turn stimulate HIV replication by augmenting viral entry. Thus, the proposed studies aim to further validate GRO-alpha and EL-8 and their receptors as targets for antiretroviral therapy. A mechanistic understanding of the interactions between HIV and these C-X-C chemokines could lead to the development of new approaches to the treatment of patients infected with HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062248-03
Application #
7160544
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2005-04-15
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
3
Fiscal Year
2007
Total Cost
$362,679
Indirect Cost
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
Mor-Vaknin, Nirit; Rivas, Miguel; Legendre, Maureen et al. (2018) High Levels of DEK Autoantibodies in Sera of Patients With Polyarticular Juvenile Idiopathic Arthritis and With Early Disease Flares Following Cessation of Anti-Tumor Necrosis Factor Therapy. Arthritis Rheumatol 70:594-605
Contreras-Galindo, Rafael; Dube, Derek; Fujinaga, Koh et al. (2017) Susceptibility of Human Endogenous Retrovirus Type K to Reverse Transcriptase Inhibitors. J Virol 91:
Mor-Vaknin, Nirit; Saha, Anjan; Legendre, Maureen et al. (2017) DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis. Nat Commun 8:14252
Gonzalez-Hernandez, Marta J; Cavalcoli, James D; Sartor, Maureen A et al. (2014) Regulation of the human endogenous retrovirus K (HML-2) transcriptome by the HIV-1 Tat protein. J Virol 88:8924-35
Saha, Anjan K; Kappes, Ferdinand; Mundade, Amruta et al. (2013) Intercellular trafficking of the nuclear oncoprotein DEK. Proc Natl Acad Sci U S A 110:6847-52
Contreras-Galindo, Rafael; Kaplan, Mark H; He, Shirley et al. (2013) HIV infection reveals widespread expansion of novel centromeric human endogenous retroviruses. Genome Res 23:1505-13
Contreras-Galindo, Rafael; Kaplan, Mark H; Contreras-Galindo, Angie C et al. (2012) Characterization of human endogenous retroviral elements in the blood of HIV-1-infected individuals. J Virol 86:262-76
Gonzalez-Hernandez, Marta J; Swanson, Michael D; Contreras-Galindo, Rafael et al. (2012) Expression of human endogenous retrovirus type K (HML-2) is activated by the Tat protein of HIV-1. J Virol 86:7790-805
Kappes, Ferdinand; Waldmann, Tanja; Mathew, Veena et al. (2011) The DEK oncoprotein is a Su(var) that is essential to heterochromatin integrity. Genes Dev 25:673-8
Mor-Vaknin, Nirit; Kappes, Ferdinand; Dick, Amalie E et al. (2011) DEK in the synovium of patients with juvenile idiopathic arthritis: characterization of DEK antibodies and posttranslational modification of the DEK autoantigen. Arthritis Rheum 63:556-67

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