A Blog Around The Clock

It's Monday afternoon, time to take a look at the brand new articles in PLoS Medicine and PLoS Biology:

Tasting the Bitter Sunlight:

Have you ever had that gut reaction to your surroundings, some physical sensation that something isn't quite right? Maybe a squirmy, uneasy feeling in your stomach or an acrid taste on your tongue that makes you want to leave the scene? When the nematode C. elegans encounters an offensive sensation--whether a pungent, potentially dangerous odor (such as those associated with fungal parasites), extreme temperature, or the poking probe of a researcher--it wastes no time in making a hasty retreat. Researchers have elucidated the mechanisms of avoidance in these tiny worms to remarkable molecular and cellular detail (a much clearer picture than the often mysterious avoidance behaviors of humans).

In a new study, Stacey L. Edwards, Kenneth G. Miller, and colleagues expand the level of our understanding by describing a striking new behavior and mechanism of sensory detection for these microscopic animals. They demonstrate that short-wavelength light, such as blue-violet and ultraviolet (UV), is a potent avoidance cue, stimulating a robust acceleration of locomotion when the tail or body is illuminated, while head illumination drives reversal locomotion. After identifying and characterizing this new behavior, Edwards et al. used classic forward genetics (whereby animals are mutagenized and screened for defective phenotypes) to identify mutants that are unresponsive to UV light. Surprisingly, the mutations mapped to a gene that encodes a protein unrelated to any of the known phototransduction systems in nature. The authors named this new protein LITE-1 and showed that it functions as a UV light receptor. Interestingly, LITE-1 is related to the large family of insect Gustatory receptors that mediate taste responses. The closest homology is to that of fly Gustatory receptors, which detect water-soluble sugars and carbon dioxide.

Can a Topical Microbicide Prevent Rectal HIV Transmission?:

Animal models are critical tools for the preclinical evaluation of drugs. Yet in the HIV field, the value of such models for predicting the success of preventive drug and vaccination strategies in humans has been disappointing. For example, animal models were unable to predict the failure of vaginal microbicides in large clinical trials in humans [1,2]. However, two recently published studies have provided encouraging results. Using a repeat, low-dose exposure macaque model, Walid Heneine and colleagues found that systemic pre-exposure prophylaxis (PrEP), using a combination of the nucleoside analogue reverse transcriptase inhibitors emtricitabine and tenofovir, protected macaques against rectal challenge with simian HIV [3]. Most prior macaque studies used single high-dose virus challenges, which are less representative of viral exposure in humans. Another study by J. Victor Garcia and colleagues introduced an improved mouse model of vaginal HIV transmission [4]. Mice engineered to stably exhibit extensive infiltration of organs and tissues, including the female reproductive tract, with a broad range of human blood cells were protected from intravaginal HIV infection by PrEP with emtricitabine/tenofovir. This mouse model opened the way for larger-scale comparative assessments in vivo, which is impossible in macaques due to the prohibitively high costs.

A third key study by Martin Cranage and colleagues is published in this issue of PLoS Medicine [5]. The researchers investigated whether rectal simian immunodeficiency virus (SIV) transmission in macaques could be prevented by the topical pre-exposure application of tenofovir gel. Rectal SIV or HIV challenge bears a much higher transmission probability than vaginal challenge. With some caveats, as discussed further below, successful prevention of rectal transmission is therefore likely to have a better predictive value for human trials than vaginal challenge models. Moreover, anal intercourse in heterosexual populations has been underestimated in the past, and means to prevent rectal HIV transmission are thus urgently needed for both women and men who have unprotected anal intercourse.