Targeting DNA Damage Response as a Strategy to Treat HPV Infections.

Mucosotropic human papillomaviruses (HPVs) cause prevalent anogenital infections, some of which can progress to cancers. It is imperative to identify efficacious drug candidates, as there are few therapeutic options. We have recapitulated a robust productive program of HPV-18 in organotypic raft cultures of primary human keratinocytes. The HPV E7 protein induces S phase reentry, along with DNA damage response (DDR) in differentiated cells to support viral DNA amplification. A number of small molecule inhibitors of DDR regulators are in clinical use or clinical trials to treat cancers. Here, we used our raft culture system to examine effects of inhibitors of ATR/Chk1 and ATM/Chk2 on HPV infection. The inhibitors impaired S-phase reentry and progression as well as HPV DNA amplification. The Chk1 inhibitor MK-8776 was most effective, reducing viral DNA amplification by 90-99% and caused DNA damage and apoptosis, preferentially in HPV infected cells. We found that this sensitivity was imparted by the E7 protein and report that MK-8776 also caused extensive cell death of cervical cancer cell lines. Furthermore, it sensitized the cells to cisplatin, commonly used to treat advanced cervical cancer. Based on these observations, the Chk1 inhibitors could be potential effective agents to be re-purposed to treat the spectrum of HPV infections in single or combination therapy.

Lack of evidence for sexual transmission of genital Candida species among women who have sex with women: a mixed methods study.

OBJECTIVE: The contribution of sexual transmission to genital Candida infection remains unclear. This study sought to investigate whether sexual behaviours were associated with the presence of genital Candida species among a cohort of women who have sex with women (WSW) in addition to determining the genetic concordance of genital Candida spp. among WSW in sexual partnerships. METHODS: WSW ≥18 years of age presenting to the Mississippi State Department of Health STD Clinic during 2009-2010 completed a sexual behaviour survey. Culture of vaginal fluid was performed for Candida spp. identification; associations with participant characteristics were determined using logistic regression analysis. Random amplified polymorphic DNA (RAPD) PCR was performed on DNA extracted from yeast cultures of WSW in sexual partnerships in which both partners had isolates of Candida spp. identified and among a set of age/sexual behaviour matched controls. RAPD genetic fingerprints were evaluated by hierarchical cluster analysis for concordance. RESULTS: Genital Candida spp. were isolated in 105/196 (53.6%) of women: 13/105 (12.4%) had symptomatic vulvovaginal candidiasis while 92/105 (87.6%) had asymptomatic vaginal colonisation. Bisexual identity, sex with women and men during the past 12 months and numbers of male sexual partners during the past 12 months were the only significant predictors of genital Candida spp. in bivariate analysis. 13 pairs of WSW in sexual partnerships in which both partners had genital Candida spp. and 11 WSW with genital Candida spp. not in sexual partnerships were identified. Candida spp. RAPD banding patterns were discordant for all isolates among WSW within partnerships and in controls. CONCLUSIONS: This study found no evidence supporting sexual transmission of genital Candida spp. between women.