HIV-1 quasispecies outsmarts us. Again.

Okay, so like, we suck at making HIV-1 vaccines. Im trying to make our vaccines more logical/efficacious/etc, but right now, we suck. No HIV-1 vaccine.

There are other ways to prevent HIV-1 infection via sex– like condoms. YAY! HIV-1 doesnt ‘swim’. It doesnt move on its own. It has to be carried by semen. But since semen cant go through a condom, YAY! No HIV-1 goes through either.

Well, condoms break. People dont always wear them right. And condoms are a male-centered HIV-prevention method. Not every woman on planet earth is in a position to say ‘Honey, put on a condom.’

So we have been trying real hard to make vaginal lubricants and such with anti-HIV-1 compounds in them. Woman-centered HIV-prevention method!

One idea has been to put PSC-RANTES in lubricants. You know how some people dont have CCR5, so they cant be infected with some kinds of HIV-1? PSC-RANTES is a compound that sticks to CCR5, kinda making all of us ‘delta CCR5′. You have to have it at really high concentrations at the site of infection for it to work well, and lubricants can do that, so researchers tried it out in macaques. At really high doses (1 mM), it was 100% effective at preventing infection.

100%.

WHOOOO!!!

No whooo.

Because while that particular experiment gave us really cool results, there are variants in the HIV-1 quasispecies that dont give a rats ass about PSC-RANTES.

Selection of a simian-human immunodeficiency virus strain resistant to a vaginal microbicide in macaques.

When normal people think about HIV-1 and how it mutates, they imagine all the sequence changing all the time. But its not really like that. There are some regions that are the same between every subtype of HIV-1. There are some regions that are totally variable in one subtype, but not another. And there are little patters, motifs, all over the place.

One such pattern is in the part of Env that binds to coreceptor (CCR5 or CXCR4 or ‘other’)– GPGX. In this region, you always see Glycine-Proline-Glycine-Anything. ‘Anything’ isnt technically anything– like HIV-1 hates lysine in that position, but theoretically it can be anything.

All HIV-1 needs to get around PSC-RANTES is GPG-Arginine.

*head desk*

The SHIV (half SIV, half HIV) used in the macaque study didnt originally have GPGR. But in the presence of sub-optimal levels of PSC-RANTES, enough replication could occur to rebuild the SHIV quasispecies. When GPGR popped up, it went to town. But most of our lab strains of HIV-1 (the ‘white mice’ of HIV-1)? They have an arginine at that fourth position. This variant is kinda stock-standard in HIV-1.

*head desk*

But real people arent lab strains– lets say you just have a mixed quasispecies. When you have less-than-optimal concentrations of PSC-RANTES (say, you wanna get it on a few hours after you first applied the drug), minority components of the HIV-1 quasispecies (GPGR) do the same damn thing that minority components of a quasispecies do when drugs are around: evolve to be highly fit and resistant to the compound.

*head desk*

Inconceivable…

Comments

#1 BAllanJ
May 19, 2009

“I don’t think that word means what you think it means”… (sorry, I had to say it) But, thanks for the lesson again.
#2 James Drexler
May 20, 2009

Another wonderfully educational post. But one small quibble:

“When normal people think about HIV-1 and how it mutates”

If your mind often drifts to HIV-1 mutations, it’s a stretch to call you a “normal person.”
#3 Ian Musgrave
May 20, 2009

Dang! We’re trying to make a “microbicide” by preventing HIV binding to certain (different, secret for patent reasons) proteins. If this holds for our target, we’re stuffef too (sighs expressively)
#4 Optimus Primate
May 20, 2009

My first reaction after reading this and looking at the comments was, “What a cool post! Why aren’t more people commenting?”

And then I realized the only comment I could come up with was bitching about why there were so few comments.

Awesome post, though. I continue to be amazed by how much I learn here.
#5 ERV
May 20, 2009

Science posts dont get a lot of comments, but dont worry, they get a lot of reads
#6 BAllanJ
May 20, 2009

And my comment up there wasn’t so much a comment on the post, but an attempt at humour by making a semi-obscure Princess Bride reference. But I did like the post… and learned something again from our wonderful erv! That makes her science posts all full of win! (and profit?!)
#7 dNorrisM
May 20, 2009

I’ve gotten to be kind of a sitemeter addict: so far,
646 hits today.

And of course, very informative article.
#8 Lou FCD
May 20, 2009

Crap.

Thanks for the post, but crap.
#9 Lou FCD
May 20, 2009

(uh, crap about the situation, not the post – just to be clear.)
#10 sublunary
May 20, 2009

Abbie,

Someone linked me to this article about another possible prevention method, which I’d love to know your opinion of. Apparently, Weill Cornell Medical College has developed a vaginal ring that is supposed to prevent pregnancy and HIV infection (and possibly other STIs as well).

They say “The compounds tested were a newly developed anti-HIV agent, Boc-lysinated betulonic acid, TMC120 (dapivirine), PMPA, and 3′-azido-3′-deoxythymidine (AZT or zidovudine), which, when combined, were found to block infection in human cells exposed to the virus in a laboratory setting.”

Does this sound realistic? Dare I raise a tiny bit of hope of this working someday?
#11 ELR
May 20, 2009

sublunary,
Things that apply in cultures in a laboratory often don’t translate to applications all up inside a lady’s bits. Also, the combination probably gives you cancer. I’m such a ray of sunshine today.
#12 sublunary
May 20, 2009

I figured there may be problems in application.

Does that drug combo really probably give you cancer? Half the article talked about how great it was as an alternative to hormonal birth control because the hormones are linked to cancer…. Figures.
#13 John Phillips, FCD
May 20, 2009

sublunary, if you read the right wingnut press in the UK, everything either causes cancer or cures it. Even better, whether something causes or cures cancer can change from one issue to the next.

P.S. Another great post Abbie.
#14 J Todd DeShong
May 23, 2009

Uhm, I just had to say that ELR made me laugh with “all up inside a lady’s bits!” Priceless.
JTD
#15 synapse
May 27, 2009

Wait, I’m confused. So, it’s clear that if you give a person a drug continuously, you’re going to be selecting for resistance quickly, because the drug is acting on the HIV all the time. However, this gel isn’t going to be used continuously; HIV is only going to encounter it during potential transmission events. During transmission events, each HIV particle either latches onto a cell and infects somebody or doesn’t- there’s no host-independent replication, right? So, the HIV isn’t going to evolve in response to the gel at all inside the original male host, and HIV in the global population is only going to evolve in response to the gel relatively slowly.

So, it still seems worth it for at least some people to use this gel. Assuming that GPGR-variants are currently a small percentage of the HIV particles in most male hosts and that the risk of any single virus particle causing an infection in a new host is relatively small, for initial adopters using this gel will substantially decrease the risk of getting HIV. (Of course, my assumptions might be totally off, in which case I stand corrected.) That will buy people time, which is very valuable. This gel also initially might be a good secondary form of protection. Of course, the population selection pressure will eventually render the gel less useful- but that will buy the researchers time as well.