Erythromycin derivatives inhibit HIV-1 replication in macrophages through modulation of MAPK activity to induce small isoforms of C/EBPbeta
| Autor: | Aikichi Iwamoto, Kiyoko S. Akagawa, Iwao Komuro, Yasuko Yokota, Satoshi Omura, Toshiaki Sunazuka |
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| Rok vydání: | 2008 |
| Předmět: |
Gene isoform
MAPK/ERK pathway CD4-Positive T-Lymphocytes Proto-Oncogene Proteins c-hck Erythromycin Biology Inhibitory postsynaptic potential Virus Replication medicine Humans Protein Isoforms Psychological repression Cells Cultured Multidisciplinary Ccaat-enhancer-binding proteins CCAAT-Enhancer-Binding Protein-beta Macrophages Biological Sciences Molecular biology Coculture Techniques Viral replication HIV-1 Disease Susceptibility Mitogen-Activated Protein Kinases medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 105(34) |
| ISSN: | 1091-6490 |
| Popis: | Macrophages (MΦs) are a major source of HIV-1 especially in patients with tuberculosis. There are MΦs that are permissive and those that restrict HIV-1. Regulation of hematopoietic cell kinase (Hck) activity and selective expression of CCAAT enhancer binding protein β (C/EBPβ) isoforms greatly contribute to determine distinct susceptibility of MΦs to HIV-1. Resistance is attributable to reduced expression of Hck and augmented expression of an inhibitory small isoform of C/EBPβ. Derivatives of erythromycin A (EMA) EM201 and EM703 inhibit the replication of HIV-1 in tissue MΦs, at posttranscriptional and translational levels. We demonstrate that EM201 and EM703 convert tissue MΦs from HIV-1 susceptible to HIV-1 resistant through down-regulation of Hck and induction of small isoforms of C/EBPβ. These drugs inhibit p38MAPK activation which is expressed only in susceptible tissue MΦs. Activated CD4 + T cells stimulate the viral replication in HIV-1 resistant MΦs through down-regulation of small isoforms of C/EBPβ via activation of ERK1/2. EM201 and EM703 can inhibit the MAPK activation and inhibit the burst of viral replication produced when CD4 + T cells and MΦs interact. These EM derivatives may be highly beneficial for repression of residual HIV-1 in the lymphoreticular system of HIV-1-infected patients and offer great promise for the creation of new anti-HIV drugs for the future treatment of AIDS patients. |
| Databáze: | OpenAIRE |
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