LMP-420, a small-molecule inhibitor of TNF-alpha, reduces replication of HIV-1 and Mycobacterium tuberculosis in human cells

被引：29

作者：

Haraguchi S. ^{[1
]}

Day N.K. ^{[1
]}

Kamchaisatian W. ^{[1
]}

Beigier-Pompadre M. ^{[2
]}

Stenger S. ^{[2
]}

Tangsinmankong N. ^{[1
]}

Sleasman J.W. ^{[1
]}

Pizzo S.V. ^{[3
]}

Cianciolo G.J. ^{[3
]}

机构：

[1] Department of Pediatrics, University of South Florida, St. Petersburg, FL 33701

[2] Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen

[3] Department of Pathology, Duke University Medical Center, Durham

来源：

AIDS Research and Therapy | / 3卷 / 1期

关键词：

Human Immunodeficiency Virus; Peripheral Blood Mononuclear Cell; Etanercept; Alveolar Macrophage; Long Terminal Repeat;

D O I：

10.1186/1742-6405-3-8

中图分类号：

学科分类号：

摘要：

Background: Co-infections of human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (M. Tb) are steadily increasing and represent a major health crisis in many developing countries. Both pathogens individually stimulate tumor necrosis factor-alpha (TNF) release from infected cells and TNF, in turn, enhances the replication of each. A recent report on a Phase 1 clinical trial suggested that etanercept (soluble TNF receptor) might be beneficial in treating HIV/M. Tb co-infected patients. We sought to determine if a small molecule inhibitor of TNF synthesis and activity could block replication of either organism and thus be a potential adjunct to existing drugs targeting these agents. Results: LMP-420, a novel anti-inflammatory agent that inhibits TNF, was tested for HIV-1 inhibition both alone and in combination with AZT (3′-azido-3-deoxythymidine). LMP-420 alone was tested against M. Tb. HIV-1 infected human peripheral blood mononuclear cells (PBMC) or M. Tb-infected human alveolar macrophages (AM) were treated with a single dose of LMP-420 and viral or bacterial replication determined after 7 or 5 days respectively. Viral replication was determined from supernatant p24 levels measured by ELISA. M. Tb replication was determined by bacterial culture of macrophage lysates. LMP-420 alone inhibited HIV replication over 7 days with an IC50 of ∼300 nM. Combination of LMP-420 with AZT doubled the level of HIV inhibition observed with AZT alone. LMP-420 alone inhibited the replication of virulent M. Tb by >80%, more than that observed with anti-TNF antibody alone. Conclusion: Inhibition of TNF with inexpensive, small-molecule, orally-active drugs may represent a useful strategy for enhancing the activity of currently-available antiviral and anti-M. Tb agents, particularly in those areas where co-infections with these pathogens act to synergistically enhance each other. © 2006 Haraguchi et al; licensee BioMed Central Ltd.

引用

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