Impact of vaginal microbiome communities on HIV antiretroviral-based pre-exposure prophylaxis (PrEP) drug metabolism

Despite the efficacy of antiretroviral-based pre-exposure prophylactics (PrEP) in men who have sex with men, studies in women have produced widely varying outcomes. Recent evidence demonstrates that vaginal microbial communities are associated with increased HIV acquisition risk and may impact PrEP efficacy. Here, we investigate the mechanisms underlying how vaginal bacteria alter PrEP drug levels and impact HIV infection rates ex vivo. Using cervicovaginal lavages (CVLs) from women with or without bacterial vaginosis (BV), we identified microbial metabolism of PrEP drugs in BV samples through LC-MS/MS analysis of soluble drug levels and metabolite formation in dual T-cell cultures. CVL samples were assessed for microbiome analysis using sequencing of bacterial 16S rRNA genes. We also observed non-Lactobacillus bacteria that are associated with BV may potentially impact PrEP efficacy through increased HIV infection rates in co-cultures containing Lactobacillus or BV bacteria, PrEP drugs, CEM-GFP cells, and HIV-1_LAI virus. Finally, we used these data to develop a novel predictive mathematical simulation modeling system to predict these drug interactions for future trials. These studies demonstrate how dysbiotic vaginal microbiota may impact PrEP drugs and provides evidence linking vaginal bacteria to PrEP efficacy in women.     

Advances in medical genetics.

Although advances in medical genetics are designed ultimately to help human beings receive better health care, they pose many problems for society. Some of these concerns are real, but others result from misunderstanding and/or misrepresentation of the true implication of certain developments in genetics. It is obvious that the geneticist must play a dual role in society as scientist and as advocate. Although such a duality or role is not easy, it is not impossible. However, it does mean that the training of the medical geneticist must include more than exposure to the scientific approach.     

Variability in response to UV-B among species and strains of Metarhizium isolated from sites at latitudes from 61 degrees N to 54 degrees S.

The effects of irradiances of 920 and 1200 mW m(-2) (biologically effective weighted irradiance) were examined in 2 Metarhizium album strains, 26 M. anisopliae strains, 1 M. flavoviride strain, and 1 M. taii strain isolated from sites located at latitudes from 61 degrees N to 54 degrees S. Conidia were exposed to UV-B from 1 to 6 h and subsequently examined for relative percentage culturability. Total dosage received at the end of the exposure periods ranged from 3.3 to 19.9 kJ m(-2) for the lower irradiance and from 4.3 to 25.9 kJ m(-2) for the higher irradiance. Both the irradiance values and the doses are environmentally realistic and can be observed even in temperate regions. The relationships between latitude of origin and UV-B tolerance were compared for the two levels of irradiance for the data from 1 and 2 h exposure. Exposure to both irradiances drastically reduced the relative percentage culturability of all strains. Tolerance to UV-B varied widely among strains and high variation was observed for both irradiances after all periods of exposure. After 1 h of exposure, a difference between the two irradiance levels was detectable, and this difference was magnified at longer irradiations. A significant quadratic relationship of decreasing UV-B tolerance with increasing latitude was observed after exposure of 1 and 2 h. The shape of the relationship did not differ for the two levels of irradiance. Also, we studied the effect of 1200 mW m(-2) irradiance on conidial germination time in 1 M. album strain, 7 M. anisopliae strains, and 1 M. taii strain. Exposure to UV-B delayed the germination of surviving conidia of all strains. In general, the delay in germination was directly proportional to the dose.     

Phytotoxicity of pheromonal chemicals to fruit tree foliage: chemical and physiological characterization.

Some recent high-load, low-density pheromone-release devices emit an ethanolic blend of pheromone directly onto crop foliage to control insect pests by mating disruption. This study characterized the phytotoxicity associated with deposition of some pheromonal compounds in concentrated drops on the foliage of trees bearing aerosol release devices. The relative toxicity of straight-chained alkanes, alcohols, aldehydes, and acetates with chain lengths varying from C-2 to approximately C-20 was quantified in the laboratory by the severity of necrotic lesions. The order of severity for phytotoxicity caused by pheromonal compounds was alkanes < acetates = aldehydes < or = alcohols. Within compound classes tested, pheromones with chain lengths of 6-13 carbons were the most phytotoxic. Phytotoxicity was not detectable at dosages <1 mg administered in 10 microl of ethanol. Phytotoxicity of pheromones was highly correlated with presence of both a hydrophilic and lipophilic molecular domain. We postulate nonspecific membrane disruption as a likely mode of action for pheromonal phytotoxicity. Limited attempts to remediate this effect by changing carrier solvents or adding surfactants, spreaders, or nonvolatile diluents were not successful. Because the toxic action of pheromones upon plant tissues appears relatively benign, and growers have not been adverse to localized phytotoxicity to foliage and fruits on two trees per 0.4 ha, we propose that limited phytotoxicity associated with first-generation aerosol dispenser technology can be viewed as non-threatening.     

Potential for transduction of plasmids in a natural freshwater environment: effect of plasmid donor concentration and a natural microbial community on transduction in Pseudomonas aeruginosa

Transduction of Pseudomonas aeruginosa plasmid Rms149 by the generalized transducing bacteriophage phi DS1 was shown to occur during a 9-day incubation of environmental test chambers in a freshwater reservoir. Plasmid DNA was transferred from a nonlysogenic plasmid donor to a phi DS1 lysogen of P. aeruginosa that served both as the source of the transducing phage and as the recipient of the plasmid DNA. When the concentration of donors introduced into the chambers was varied while the recipient concentration in each chamber was at a level equivalent to natural concentrations of P. aeruginosa, the concentration of plasmid-containing donor cells introduced was shown to affect the frequency of transduction significantly. Transduction was observed both in the absence and in the presence of the natural microbial community. The presence of the natural community resulted in a rapid decrease in the numbers of the introduced donors and recipients and a decrease in the number of transductants recovered. These results demonstrate the potential for naturally occurring transduction in aquatic environments and indicate that donor load may be an important parameter in assessing this potential.