Abstract

BackgroundCo-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.ResultsLMP-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.ConclusionInhibition 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.

Highlights

  • Co-infections of human immunodeficiency virus (HIV) and Mycobacterium tuberculosis

  • Since tumor necrosis factor-alpha (TNF) released from LPS-stimulated peripheral blood mononuclear cells (PBMC) is derived mostly from monocytes/macrophages, we wanted to determine if LMP-420 could inhibit TNF release from stimulated lymphocytes

  • Since LMP-420 inhibits TNF release from PBMC stimulated with a variety of ligands other than LPS we assumed that inhibition was occurring at a post-stimulus step

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Summary

Introduction

Co-infections of human immunodeficiency virus (HIV) and Mycobacterium tuberculosis 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. Of the >40 million adults and 5 million children infected with HIV, 95 percent live in developing countries and about one-third are co-infected with M. Tb. As many as half of HIV-infected patients in Africa have M. People co-infected with both HIV and M. Tb have a 100-fold greater risk of developing active M. Tb goes untreated in HIV+ patients, most will die within one year

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