title: In vitro model of mycobacteria and HIV-1 co-infection for drug discovery.
abstract: Tuberculosis (TB) has become a global health threat in the wake of the Human Immunodeficiency Virus (HIV) pandemic and is the leading cause of death in people with HIV/AIDS. Treatment of patients with Mycobacterium tuberculosis (Mtb)/HIV co-infection is complicated by drug interactions and toxicity that present huge challenges for clinical intervention. Discovery efforts to identify novel compounds with increased effectiveness and decreased drug-drug interactions against Mtb, HIV-1, or both, would be greatly aided by the use of a co-infection model for screening drug libraries. Currently, inhibitors of Mtb are screened independently in mycobacterial cell cultures or target based biochemical screens and less often in macrophages or peripheral blood leukocytes. Similarly, HIV-1 drugs are screened in vitro independently from anti-mycobacterial compounds. Here, we describe an in vitro model where primary human peripheral blood mononuclear cells or monocyte-derived macrophages are infected with Mycobacterium bovis BCG and HIV-1, and used to evaluate drug toxicity and activity in a co-infection setting. Our results with standard compounds (e.g. Azidothymidine, Rifampicin) demonstrate the utility of this in vitro model to evaluate drug effectiveness relevant to cellular toxicity, HIV-1 replication, and intracellular mycobacterial growth, through the use of ELISA, bacterial enumeration, and multi-variate flow cytometry. This model and associated assays have great value in accelerating the discovery of compounds for use in Mtb/HIV-1 co-infected patients.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Sudhamathi
authors.initials: S
authors.lastname: Vijayakumar
authors.affiliation: Department of Pharmaceutical Sciences, Texas Southern University, Houston, TX, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Finney John
authors.affiliation: Institute for Translational Science, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Nusbaum
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Monique R
authors.initials: MR
authors.lastname: Ferguson
authors.affiliation: Department of Microbial Pathogenesis and Immunology Texas A&M Health Sciences Center, College Station, TX, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Cirillo
authors.affiliation: Department of Pharmaceutical Sciences, Texas Southern University, Houston, TX, USA.
authors.forename: Omonike
authors.initials: O
authors.lastname: Olaleye
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infections and Immunity, Center for Tropical Diseases, Sealy Center for Vaccine Development, and Center for Biodefense and Emerging Infectious Diseases, UTMB, Galveston, TX, USA. Electronic address: jjendsle@utmb.edu.
authors.forename: Janice J
authors.initials: JJ
authors.lastname: Endsley
mesh_terms: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D060085:Coinfection; D055808:Drug Discovery / Q000639:trends; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents
keywords: Drug interactions; Drug screening; HIV; In vitro model; TB