Erythromycin derivatives inhibit HIV-1 replication in macrophages through modulation of MAPK activity to induce small isoforms of C/EBPbeta.
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.
Komuro
Iwao
I
Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
Sunazuka
Toshiaki
T
Akagawa
Kiyoko S
KS
Yokota
Yasuko
Y
Iwamoto
Aikichi
A
Omura
Satoshi
S
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000187:drug effects / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004198:Disease Susceptibility; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000821:virology*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects*; D020033:Protein Isoforms; D051572:Proto-Oncogene Proteins c-hck / Q000187:drug effects / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
D022782:CCAAT-Enhancer-Binding Protein-beta; C509870:EM703; D020033:Protein Isoforms; C093673:8,9-anhydroerythromycin A 6,9-hemiketal; D004917:Erythromycin; D051572:Proto-Oncogene Proteins c-hck; D020928:Mitogen-Activated Protein Kinases