title: Activity of a novel combined antiretroviral therapy of gemcitabine and decitabine in a mouse model for HIV-1.
abstract: The emergence of drug resistance threatens to limit the use of current anti-HIV-1 drugs and highlights the need to expand the number of treatment options available for HIV-1-infected individuals. Our previous studies demonstrated that two clinically approved drugs, decitabine and gemcitabine, potently inhibited HIV-1 replication in cell culture through a mechanism that is distinct from the mechanisms for the drugs currently used to treat HIV-1 infection. We further demonstrated that gemcitabine inhibited replication of a related retrovirus, murine leukemia virus (MuLV), in vivo using the MuLV-based LP-BM5/murine AIDS (MAIDS) mouse model at doses that were not toxic. Since decitabine and gemcitabine inhibited MuLV and HIV-1 replication with similar potency in cell culture, the current study examined the efficacy and toxicity of the drug combination using the MAIDS model. The data demonstrate that the drug combination inhibited disease progression, as detected by histopathology, viral loads, and spleen weights, at doses lower than those that would be required if the drugs were used individually. The combination of decitabine and gemcitabine exerted antiviral activity at doses that were not toxic. These findings indicate that the combination of decitabine and gemcitabine shows potent antiretroviral activity at nontoxic doses and should be further investigated for clinical relevance.
authors.affiliation: Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Clouser
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Holtz
authors.forename: Mary
authors.initials: M
authors.lastname: Mullett
authors.forename: Daune L
authors.initials: DL
authors.lastname: Crankshaw
authors.forename: Jacquie E
authors.initials: JE
authors.lastname: Briggs
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
authors.forename: Louis M
authors.initials: LM
authors.lastname: Mansky
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D000077209:Decitabine; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D011533:Proviruses / Q000187:drug effects; D013154:Spleen / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000187:drug effects; D014162:Transfection; D000093542:Gemcitabine
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D003841:Deoxycytidine; D000077209:Decitabine; D001374:Azacitidine; D000093542:Gemcitabine