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

Proceedings of the National Academy of Sciences of the United States of America
Iwao KomuroSatoshi Omura

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 h...Continue Reading

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Citations

Apr 9, 2010·Retrovirology·Anna Bergamaschi, Gianfranco Pancino
Mar 31, 2009·Future Microbiology·Yujie LiuBrian Wigdahl
Oct 1, 2015·The Journal of Antibiotics·Akihiro SugawaraToshiaki Sunazuka
Dec 21, 2014·Blood·Christel VérolletIsabelle Maridonneau-Parini
Dec 7, 2010·Biotechnology Advances·Preeti Vaishnav, Arnold L Demain
Oct 13, 2011·Scandinavian Journal of Immunology·A S SahlbergM A Penttinen
Mar 9, 2012·Expert Review of Anti-infective Therapy·Marie-Thérèse Labro
May 22, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Christel VérolletIsabelle Maridonneau-Parini
Aug 11, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Jingjing WanXia Liu

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