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

• Main Authors: Tangsinmankong Nutthapong, Stenger Steffen, Beigier-Pompadre Macarena, Kamchaisatian Wasu, Day Noorbibi K, Haraguchi Soichi, Sleasman John W, Pizzo Salvatore V, Cianciolo George J
• Format: Article
• Language: English
• Published: BMC 2006-03-01
• Series: AIDS Research and Therapy
• Online Access: http://www.aidsrestherapy.com/content/3/1/8

<p>Abstract</p> <p>Background</p> <p>Co-infections of human immunodeficiency virus (HIV) and <it>Mycobacterium tuberculosis </it>(<it>M. Tb</it>) 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/<it>M. Tb </it>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.</p> <p>Results</p> <p>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 <it>M. Tb</it>. HIV-1 infected human peripheral blood mononuclear cells (PBMC) or <it>M. Tb</it>-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. <it>M. Tb </it>replication was determined by bacterial culture of macrophage lysates. LMP-420 alone inhibited HIV replication over 7 days with an IC₅₀of ~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 <it>M. Tb </it>by >80%, more than that observed with anti-TNF antibody alone.</p> <p>Conclusion</p> <p>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-<it>M. Tb </it>agents, particularly in those areas where co-infections with these pathogens act to synergistically enhance each other.</p>