Erythromycin derivatives inhibit HIV-1 replication in macrophages through modulation of MAPK activity to induce small isoforms of C/EBPbeta.

Abstract

Macrophages (MPhis) are a major source of HIV-1 especially in patients with tuberculosis. There are MPhis that are permissive and those that restrict HIV-1. Regulation of hematopoietic cell kinase (Hck) activity and selective expression of CCAAT enhancer binding protein beta (C/EBPbeta) isoforms greatly contribute to determine distinct susceptibility of MPhis to HIV-1. Resistance is attributable to reduced expression of Hck and augmented expression of an inhibitory small isoform of C/EBPbeta. Derivatives of erythromycin A (EMA) EM201 and EM703 inhibit the replication of HIV-1 in tissue MPhis, at posttranscriptional and translational levels. We demonstrate that EM201 and EM703 convert tissue MPhis from HIV-1 susceptible to HIV-1 resistant through down-regulation of Hck and induction of small isoforms of C/EBPbeta. These drugs inhibit p38MAPK activation which is expressed only in susceptible tissue MPhis. Activated CD4(+)T cells stimulate the viral replication in HIV-1 resistant MPhis through down-regulation of small isoforms of C/EBPbeta 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 MPhis 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.

• Authors: Iwao Komuro, Toshiaki Sunazuka, Kiyoko S Akagawa, Yasuko Yokota, Aikichi Iwamoto, Satoshi Omura
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 34 Pg. 12509-14 (Aug 26 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18719105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCAAT-Enhancer-Binding Protein-beta
• EM703
• Protein Isoforms
• 8,9-anhydroerythromycin A 6,9-hemiketal
• Erythromycin
• Proto-Oncogene Proteins c-hck
• Mitogen-Activated Protein Kinases

Topics

• CCAAT-Enhancer-Binding Protein-beta (drug effects, genetics)
• CD4-Positive T-Lymphocytes (virology)
• Cells, Cultured
• Coculture Techniques
• Disease Susceptibility
• Erythromycin (analogs & derivatives, pharmacology)
• HIV-1 (drug effects, genetics)
• Humans
• Macrophages (virology)
• Mitogen-Activated Protein Kinases (drug effects)
• Protein Isoforms
• Proto-Oncogene Proteins c-hck (drug effects, genetics)
• Virus Replication (drug effects)