The Candida albicans CDR1 gene, encoding an ABC transporter that functions as an efflux pump, is thought to be involved in pathogenic adaptation and uses mammalian hormones and other environmental cues to regulate its activity. Exposure of several clinical isolates of C. albicans to 1 × 10 −8 M 17β-oestradiol increased CDR1 expression and the isolates showed a positive correlation between oestrogen induction of CDR1 and growth in the presence of oestrogen. A reporter strain carrying the GFP gene under the control of the CDR1 promoter was used to analyse the effect of steroid hormones and antifungal drugs on CDR1 expression by flow cytometry. We found that among the many hormones tested, only oestradiol and progesterone induce CDR1 expression. CDR1 induction requires hormone concentrations greater than 10 −8 M, a threshold reached in vivo only by progesterone. Using the GFP-reporter strain, we show CDR1 induction by female but not male human serum and demonstrate that exposure of C. albicans to physiological concentrations of progesterone measurably increases resistance to fluconazole, miconazole and 5-fluorouracil. Simultaneous exposure of C. albicans to hormones and antifungal drugs provided evidence that both agents induce CDR1 expression via different mechanisms with different saturation points.
Human papillomavirus (HPV)-specific T-cell response to the HPV type 16 (HPV16) E6 protein has been shown to be associated with successful viral clearance. The patterns of CD8 T-cell epitopes within HPV16 E6 protein were previously studied in two women with HPV16 clearance. The goal of this study was to characterize these epitopes in terms of their minimal and optimal amino acid sequences and the human leukocyte antigen (HLA) restriction molecules. The presence of the epitope-specific memory T cells after viral clearance was also examined. In subject A, the dominant epitope was characterized to be E6 75-83 (KFYSKISEY), restricted by the HLA-B62 molecule, while that of subject B was E6 133-142 (HNIRGRWTGR), restricted by the HLA-A6801 molecule. Homologous epitopes were identified in five other high-risk HPV types for both of these epitopes, but they were not recognized by respective T-cell clone cells. An enzyme-linked immunospot assay or tetramer analysis was performed on peripheral blood mononuclear cells from blood samples collected after viral clearance but prior to isolation of the T-cell clones. The presence of epitope-specific memory T cells was demonstrated. These data suggest that HPV-specific memory T cells were generated in vivo and that they may remain in circulation many months, if not years, after viral clearance. Our findings broaden the spectrum of the CD8 T-cell epitopes of the HPV16 E6 protein. The characterization of novel T-cell epitopes and long-lasting epitope-specific memory T cells may be useful for the development of a potential epitope-based vaccine.Cervical cancer is the second most common malignant cancer in women worldwide. High-risk human papillomaviruses (HPVs), most commonly HPV type 16 (HPV16), have been shown as the major cause of cervical cancer (29, 33). The transforming properties of high-risk HPV16 E6 and E7 proteins play a critical role in the initiation of oncogenic processes. The E6 protein can lead to the degradation of the p53 tumor suppressor protein (4, 28), while the E7 protein can interfere with the retinoblastoma tumor suppressor protein (28). These two proteins are foreign viral antigens, and their constitutive expression is required for the maintenance of the malignant phenotype of cervical cancer (32, 33). Therefore, HPV16 E6 and E7 proteins have been sought as ideal targets of antigenspecific immunotherapeutic strategies for the prevention and treatment of cervical cancer.Immune responses, especially HPV-specific T-cell immune responses, are thought to play an important role in successfully clearing HPV infection and controlling HPV-associated diseases. CD8-positive, major histocompatibility complex class I-restricted cytotoxic T lymphocytes (CTLs) are known to be responsible for recognizing and killing virus-infected host cells and virus-induced tumor cells (12). Immunohistochemical analyses of squamous intraepithelial lesion and cervical cancer specimens have demonstrated the presence of activated CTLs in lesions (2). A study using stimulated peripheral blood m...
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