Summary Background Hsp90 is an environmentally contingent molecular chaperone that influences the form and function of diverse regulators of cellular signaling. Hsp90 potentiates the evolution of fungal drug resistance by enabling crucial cellular stress responses. Here we demonstrate that in the leading fungal pathogen of humans, Candida albicans, Hsp90 governs cellular circuitry required not only for drug resistance but also for the key morphogenetic transition from yeast to filamentous growth that is crucial for virulence. This transition is normally regulated by environmental cues, such as exposure to serum, that are contingent upon elevated temperature to induce morphogenesis. The basis for this temperature dependence has remained enigmatic. Results We show that compromising Hsp90 function pharmacologically or genetically induces a transition from yeast to filamentous growth in the absence of external cues. Elevated temperature relieves Hsp90-mediated repression of the morphogenetic program. Hsp90 regulates morphogenetic circuitry by repressing Ras1-PKA signaling. Modest Hsp90 compromise enhances the phenotypic effects of activated Ras1 signaling while deletion of positive regulators of the Ras1-PKA cascade blocks the morphogenetic response to Hsp90 inhibition. Consistent with the requirement for morphogenetic flexibility for virulence, depletion of C. albicans Hsp90 attenuates virulence in a murine model of systemic disease. Conclusions Hsp90 governs the integration of environmental cues with cellular signaling to orchestrate fungal morphogenesis and virulence, suggesting new therapeutic strategies for life-threatening infectious disease. Hsp90’s capacity to govern a key developmental program in response to temperature change provides a new mechanism that complements the elegant repertoire that organisms utilize to sense temperature.

The molecular chaperone Hsp90 regulates morphogenesis of the leading human fungal pathogen Candida albicans. Hsp90 inhibition induces filaments with a delay in mitotic exit mediated by the checkpoint protein Bub2. Hsp90 depletion destabilizes the cyclin-dependent kinase Cdc28, providing a link between Hsp90, cell cycle regulation, and morphogenesis.

Recent evidence has demonstrated the efficacy of pre-exposure prophylaxis (PrEP) for HIV prevention, but concerns persist around its use. Little is known about Canadian physicians' knowledge of and willingness to prescribe PrEP. We disseminated an online survey to Canadian family, infectious disease, internal medicine, and public health physicians between September 2012–June 2013 to determine willingness to prescribe PrEP. Criteria for analysis were met by 86 surveys. 45.9% of participants felt “very familiar” with PrEP, 49.4% felt that PrEP should be approved by Health Canada, and 45.4% of respondents were willing to prescribe PrEP. Self-identifying as an HIV expert (odds ratio, OR = 4.1, 95% confidence interval, CI = 1.6–10.2), familiarity with PrEP (OR = 5.0, 95%CI = 1.3–19.0) and having been asked by patients about PrEP (OR = 4.0, 95%CI = 1.5–10.5) were positively associated with willingness to prescribe PrEP on univariable analysis. The latter two were the strongest predictors on multivariate analysis. Participants cited cost and efficacy as major concerns. 75.3% did not feel that information had been adequately disseminated among physicians. In summary, Canadian physicians demonstrate varying levels of support for PrEP and express concerns about its implementation. Further research on real-world effectiveness, continuing medical education, and clinical support is needed to prepare physicians for this prevention strategy.

Pre-exposure prophylaxis (PrEP) has been shown to reduce the risk of HIV transmission but has the potential to cause harm if not used properly. Pharmacists are well-positioned to foster PrEP's efficacy but little is known whether they would endorse it as an HIV prevention tool. The objective of the study was to determine Canadian HIV pharmacists' support for PrEP and to identify current barriers to promoting PrEP. Canadian pharmacists with experience in HIV care were invited to complete an online survey about their experiences, opinions, and learning needs regarding PrEP from December 2012 to January 2013. Among the 59 surveys received, 48 met criteria for final analysis. Overall, 33 (69%) respondents would provide education positively supporting the use of PrEP and 26 (54%) believed Health Canada should approve PrEP for use in Canada. Familiarity with the concept of PrEP and practice characteristics examined did not appear to be significantly associated with support for PrEP in univariable analyses. The principal barriers to promoting PrEP included inadequate drug coverage and insufficient knowledge to educate others. Many Canadian HIV pharmacists would endorse PrEP for high-risk patients; however, wider dissemination of information and lower drug costs may be needed to make PrEP more widely promoted.

Oral daily tenofovir/emtricitabine (Truvada) is approved in the United States for HIV preexposure prophylaxis (PrEP) but has generated controversy in the media and within HIV-affected communities. We conducted an online survey about PrEP-related knowledge, experience, opinions, and learning needs, and received 160 responses from service providers at Canadian AIDS Service Organizations. Respondents were cautiously optimistic about PrEP and 48.8% believed that PrEP warranted Health Canada approval. In multivariable logistic regression, support for PrEP approval was associated with more years working in HIV (odds ratio = 1.89 per decade, 95% CI = 1.10, 3.25), low baseline familiarity with PrEP (OR = 3.24, 95% CI = 1.01, 14.41), and knowing someone who had used PrEP (OR = 4.39, 95% CI = 1.28,15.08). Participants major concerns about PrEP were similar to those highlighted in other publications, and some issues specific to certain target populations were raised. Several participants (26.2%) had been asked about PrEP in the past year and 10.6% knew of one or more Canadian who had used PrEP. Despite clients' interest, most participants thought that they (60.6%) or their organization (63.1%) did not have enough current knowledge about PrEP, highlighting the need for further education on this novel HIV prevention strategy.