AIDS Research and Therapy (Mar 2006)

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

  • Tangsinmankong Nutthapong,
  • Stenger Steffen,
  • Beigier-Pompadre Macarena,
  • Kamchaisatian Wasu,
  • Day Noorbibi K,
  • Haraguchi Soichi,
  • Sleasman John W,
  • Pizzo Salvatore V,
  • Cianciolo George J

DOI
https://doi.org/10.1186/1742-6405-3-8
Journal volume & issue
Vol. 3, no. 1
p. 8

Abstract

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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.