Research

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

Soichi Haraguchi¹ , Noorbibi K Day¹ , Wasu Kamchaisatian¹ , Macarena Beigier-Pompadre² , Steffen Stenger² , Nutthapong Tangsinmankong¹ , John W Sleasman¹ , Salvatore V Pizzo³ and George J Cianciolo³

¹  Department of Pediatrics, University of South Florida, 801 Sixth Street South, St. Petersburg, FL 33701, USA

²  Institut für Klinische Mikrobiologie, Immunologie und Hygiene der Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

³  Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA

author email corresponding author email

AIDS Research and Therapy 2006, 3:8doi:10.1186/1742-6405-3-8

Published:	31 March 2006

Abstract

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 I 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.