RESUMO
Human endogenous retroviruses (HERVs) make up 8% of the human genome. The expression of HERV-K (HML-2), the family of HERVs that most recently entered the genome, is tightly regulated but becomes markedly increased after infection with HIV-1. To better understand the mechanisms involved in this activation, we explored the role of the HIV-1 Tat protein in inducing the expression of these endogenous retroviral genes. Administration of recombinant HIV-1 Tat protein caused a 13-fold increase in HERV-K (HML-2) gag RNA transcripts in Jurkat T cells and a 10-fold increase in primary lymphocytes, and the expression of the HERV-K (HML-2) rec and np9 oncogenes was also markedly increased. This activation was seen especially in lymphocytes and monocytic cells, the natural hosts for HIV-1 infection. Luciferase reporter gene assays demonstrated that the effect of Tat on HERV-K (HML-2) expression occurred at the level of the transcriptional promoter. The transcription factors NF-κB and NF-AT contribute to the Tat-induced activation of the promoter, as shown by chromatin immunoprecipitation assays, mutational analysis of the HERV-K (HML-2) long terminal repeat, and treatments with agents that inhibit NF-κB or NF-AT activation. These studies demonstrate that HIV-1 Tat plays an important role in activating expression of HERV-K (HML-2) in the setting of HIV-1 infection.
Assuntos
Retrovirus Endógenos/fisiologia , Regulação Viral da Expressão Gênica , Produtos do Gene env/biossíntese , Infecções por HIV/metabolismo , HIV-1/metabolismo , Proteínas do Envelope Viral/biossíntese , Ativação Viral , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene env/genética , Infecções por HIV/genética , HIV-1/genética , Humanos , Células Jurkat , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas do Envelope Viral/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacologiaRESUMO
Oropharyngeal candidiasis is a very common localized infection of the mucus membranes of the oropharynx that is most commonly caused by the patient's own commensal Candida albicans. It is the most common opportunistic infection affecting patients with the human immunodeficiency virus (HIV) and is also quite common in patients with hematological malignancies. Effective treatment options are of high importance given the worldwide incidence of these disease states and the potential for development of oropharyngeal candidiasis in these patients. Various systemic and topical treatment options for patients with oropharyngeal candidiasis have existed for many years. Miconazole buccal tablets have recently been approved by the US Food and Drug Administration for the treatment of oropharyngeal candidiasis. Clinical trials have demonstrated noninferiority in the treatment of oropharyngeal candidiasis when compared with clotrimazole troches in patients with HIV and against miconazole gel in patients with head and neck cancer. Miconazole buccal tablets exhibit few drug interactions because of low systemic absorption and are generally well tolerated with a safety profile similar to comparators. The once-daily dosing schedule may improve patient adherence compared with topical alternatives; however, the cost of therapy may be a barrier for some patients and should be considered by prescribers compared with alternative treatments.