title: HIV-1 replication in monocyte-derived dendritic cells is stimulated by melarsoprol, one of the main drugs against human African trypanosomiasis.
abstract: Human African trypanosomiasis (HAT) is a disease caused by the protozoan parasite Trypanosoma brucei, the causative agent of sleeping sickness that is still endemic in well defined regions of sub-Saharan Africa. Co-infections with this human pathogen and human immunodeficiency virus (HIV) are not uncommon, but their potential interaction has been little studied. The organo-arsenical drug melarsoprol has been widely used for the treatment of late stage trypanosomiasis since the early 1950s and is still widely used despite very serious adverse effects. Because arsenic trioxide, another trivalent arsenical structurally related to melarsoprol, has been shown to markedly increase HIV replication in dendritic cells (DCs), we tested the effect of melarsoprol on virus replication in various primary human immune cell types, including DCs. We show here that this medicinal drug stimulates the replication of several strains of HIV-1, specifically in monocyte-derived DCs, and also renders such cells susceptible to HIV-2 infection. The drug acts mainly through an increase in the efficacy of the reverse transcription process, and this effect is mediated, at least partly, by an inhibition of expression of the cellular restriction factor APOBEC3G. These observations raise concerns about the harmful effect that melarsoprol might exert on the natural history of HIV in co-infected patients and on virus transmission.
authors.affiliation: Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec-CHUL, and Département de Microbiologie-Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Québec (QC), Canada.
authors.forename: Corinne
authors.initials: C
authors.lastname: Barat
authors.forename: Jacques
authors.initials: J
authors.lastname: Pepin
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Tremblay
mesh_terms: D000071480:APOBEC-3G Deaminase; D002454:Cell Differentiation / Q000187:drug effects; D003564:Cytidine Deaminase / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000821:virology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008549:Melarsoprol / Q000494:pharmacology* / Q000627:therapeutic use*; D009000:Monocytes / Q000166:cytology*; D014353:Trypanosomiasis, African / Q000188:drug therapy*; D015854:Up-Regulation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D016898:Interferon-alpha; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase; D008549:Melarsoprol