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January 28, 2009 9:37 PM   Subscribe

Recent work by Yichao Wu, Judy Lieberman, and Deborah Palliser has led to a topical treatment that knocks out the herpes virus in testing with mice by way of RNA interference (RNAi). Notably, it works when applied prior to or after sexual contact and holds promise for human usage. (RNAi is a very recent (1998) discovery that garnered the 2006 Nobel prize [MetaFilter thread] for Fire and Mello.) You can read more about the intravaginal application of siRNAs in the January issue of Cell Host & Microbe.
posted by shadytrees (9 comments total) 9 users marked this as a favorite

 
Will it rid my hideous mug of cold sores?
posted by You Should See the Other Guy at 9:40 PM on January 28, 2009 [1 favorite]


So what you're saying is that if applied just after exposure, it prevents infection. Right? Which has nothing whatever to do with curing someone who already has it?
posted by Chocolate Pickle at 10:07 PM on January 28, 2009


They discuss that in this podcast....
posted by empath at 10:07 PM on January 28, 2009


Intravaginal? How about extracockal? There is love for both sides with this discovery right?
posted by jellywerker at 10:17 PM on January 28, 2009


Man they got my hopes up and everything. Seriously, cold sores are the bane of my existance.
posted by Sargas at 10:19 PM on January 28, 2009


Some of the genes and proteins related to the RNAi mechanism have been studied in model organisms before 1998, beginning indirectly as far back as the early 1980s. Chalfie et al., 1981 and Lee et al., 1993 had shown through mutation studies that lin-4 plays an important role in regulating the development of the nematode C. elegans, through genes turned off by small RNA fragments.

Further genetic studies by Ambros, 2000; Abrahante et al., 2003; Lin et al., 2003; Ruvkun et al., 1989 and Vella et al., 2004 showed that let-7 and lin-4 were key regulatory elements that operate during various developmental stages of larval C. elegans, and, in particular, identified let-7 and lin-4 as miRNA genes.

The mRNA is a precursor of sorts that gets translated into proteins, like your hair, nails, the collagen in your skin, etc. Controlling mRNA levels is part of the way your body controls the manufacture of these and other end products. These tiny RNA fragments bind to the mRNA and through certain mechanisms prevent it from getting translated into proteins.

The prior model for the mechanism of miRNAs suggested that fully complementary binding of a miRNA to the 3' untranslated regions (UTRs) of its target caused destabilization and degradation of the target mRNA, while partial complementary binding of the miRNA to the target caused translational repression, but did not cause mRNA destabilization. Bagga et al. 2005, however, presented evidence that C. elegans let-7 and lin-4 miRNAs in fact cause a significant, measurable decrease in certain target mRNA transcripts (and an according quantitative effect on the amount of protein present), despite imperfect complementarity between the miRNA and target binding sequences, which conflicted with this prior model. A number of proteins are involved and studies continue about how all of this works, exactly.

In addition to the therapeutic application described above, RNAi is also a good laboratory technique for "knockout" studies: you apply RNAi to the organism you're studying, which lowers the amount of specific mRNA and can, for example, pull down how much end product is made — "knocking out" a protein, so to speak. Through "reverse genetics" you can indirectly poke around and find out how an organism works by shutting down bits and pieces and seeing what parts of the machinery still work and which do not.
posted by Blazecock Pileon at 10:26 PM on January 28, 2009 [5 favorites]


Chocolate pickle: "An ideal drug would also prevent viral replication in the dorsal
root ganglion viral reservoir."


The authors make token mention of the fact that HSV hides out in ganglia, and reactivates episodically to cause cold sores in mucosal tissue. Since the main problem facing HSV sufferers is reactivation from these neural ganglia, and not new invasions, I wouldn't conclude this treatment would help the already infected with their symptoms. It could help prevent asymptomatic vaginal shedding of virus.

Note that much of the HSV genome is devoted to subverting and controlling the host organism's immune system - these anti-primate immune system genes don't work properly in rodent models, thus the virus is already starting out "crippled" in mouse studies.

This is an interesting approach but is more of an advert for topical siRNAs than a real anti-HSV treatment for genital herpes. However, the topical siRNA approach seems like it might work well for HSV keratitis or AIDS-related CMV retinitis (both are caused by herpesvirus family members and infect the eyes).
posted by benzenedream at 12:37 AM on January 29, 2009 [1 favorite]


Although the news of successful topical siRNA delivery is pretty exciting, the authors of the linked paper seem a bit careless with respect to possible effects on the immune system. I worked in an RNAi lab for a few months, and inflammation was definitely something that had to be considered, especially when doing an antiviral study. False positives are not unheard of, because double-stranded RNA like siRNA can activate the innate immune system, resulting in what seems like anti-viral activity but is simply a natural consequence of the body's immune defenses.

What's more, although they cite this paper (Misinterpreting the therapeutic effects of siRNA caused by immune stimulation, Robbins et al.) in their paragraph rebutting the possibility of siRNA-caused inflammatory responses, I wonder how thoroughly they read it. The Robbins paper specifically points out that:

a) The GFP siRNA commonly used as a control is much less immunostimulatory than standard siRNA, and so it isn't very useful for avoiding the sort of false positives I mentioned above; Wu et al. used a GFP siRNA anyways, although it's possible that they used one with a different sequence.

b) More damningly, the timepoint at which cytokine response is assayed is critical:

"In our experience, both the IFNα and inflammatory cytokine response to lipidic or PEI-complexed siRNA formulations is transient, typically peaking between 2 – 8 h and fully resolving within 24 h after administration ((Judge and MacLachlan, 2008), data not shown). It is most likely therefore that any assessment of IFNα at a single 24 h timepoint will fail to detect this type of response." (emphasis mine).

In the Wu paper, though, their only analysis of possible immune upregulation was to check "samples harvested 24 hr after the second dose" and conclude that "[interferon-response] genes also were not significantly induced".

With all that taken into account, I'm with benzenedream on this one - the interesting part is that they got successful topical delivery, and I think it's a long way off from being an actual HSV prophylactic.
posted by daelin at 2:05 AM on January 29, 2009 [3 favorites]


Boobies!
Sorry, reading this thread made me feel like a stupid 10 yr old
posted by Goofyy at 6:08 AM on January 29, 2009


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