Gene therapy for fighting HIV-1: Using bacterial genes to fight viruses

There are lots of ways a scientific paper can make me laugh.

Sometimes I lol because the research is just so goddamn stupid.

Sometimes I lol in derision.

And rarely, I lol when someone does something conceptually simple, but incredibly clever, and it makes me happy. I read an abstract, laugh, read the rest of the paper, laugh, clap, and laugh. Clever people make me happy :)

This is a really clever paper:

Acquisition of HIV-1 Resistance in T Lymphocytes Using an ACA-Specific E. coli mRNA Interferase

A while back, I talked about a cell line I use in the lab called 'TZM-bl'. These cells express HIV-1 receptor (CD4), and co-receptors (CCR5 and CXCR4), and have one more really neat feature: they have been genetically modified so that their genome contains the HIV-2 promoter which drives the production of two reporter enzymes (one makes infected cells glow, one makes them turn blue, when given the right substrates).

If TZM-bl cells are infected with HIV-1, the HIV-1 Tat protein will go to the nucleus of the TZMs, 'see' the HIV-2 promoter, and say 'YAY! THAT is where IM supposed to go! LA-LA-LA-LA-LA-LA!'. This drives the production of the reporter enzymes in infected cells.

Its a useful tool in the laboratory.

... Why dont we turn the concept into something that is useful in the clinic... ?

Long-time readers of ERV know that I am not at all impressed with the idea of gene therapy as a viable real-world therapy for HIV-1 infection/prevention. We could yank CCR5 off the surface of HIV-1 target cells (though its worked in transplant form, it could theoretically work in an artificial gene therapy form). We could force B-cells to express a SUPER AWESOME anti-HIV antibody (and pray there is nothing in the quasispecies that can escape, LOL).

But these folks had a really simple, really clever idea:

What if we, like, make T-cells that like, have an anti-HIV alarm system, or something? Like, when they get infected with HIV-1, that turns on something that kills HIV-1?



Yes... Assuming you could do that, what if you do that?


Im not being sarcastic! This idea is incredible in its simplicity!

They took the basics of TZM-bls (transcription of genes driven by the HIV-2 promoter, only works if Tat is there), and changed it a bit. Made cells with the HIV-1 promoter driving the transcription of a suicide gene from E. coli (!!!), mazF. mazF chops up RNA.

So when these genetically modified T-cells were infected with HIV-1, the Tat protein saw the artificial 'HIV-1 promoter', said 'YAY! PROMOTER! YAY ME!'. Tat goes on to help make mazF:

The resulting induction of MazF expression leads to the cleavage of newly emerged HIV-1 mRNAs so that Tat protein synthesis is no longer sustainable. However, it is important to note that HIV-1 infection does not hamper cell growth and that the HIV-1 provirus genome is retained in the MazF-transduced cells. Therefore, the cellular level of Tat appears to be maintained at a very low level so that the level of MazF induction is also kept very low enough to cleave HIV-1 mRNAs, but not cellular mRNAs.

This only results in an infected cell making a tiny bit of mazF. Its not enough to kill the cell (not really what you want in someone who does not have a lot of T-cells), but its enough to keep the HIV-1 that got into the cell from making any baby viruses.




Thats awesome!

I mean, this still has all of the problems inherent in gene-therapy/bone-marrow transplants/etc-- but Im much more excited about a general 'anti-HIV' strategy like this than the others that have been proposed thus far (which might only be very solvable problems, to a quasispecies).

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Long time lurker, first time commenter. I can't seem to be able to get access to the paper through my university.
Although I thought this was done before. If not, in hindsight, it is simple to see how this could have been thought of. Two questions:
1) Are you aware of any other putative HIV therapies/control mechanisms that use bacteria (whole or otherwise)?
2) Do the authors (or you) know of any mechanism whereby the Tat protein would not evolve specificity for the HIV-1 promoter but not the HIV-2 promoter?

Dude, that's awesome! I love it when science is smart!

By JustaTech (not verified) on 01 Feb 2011 #permalink

Ooh, here's a thought. T cells which express receptors making them very susceptible to HIV infection, and also have this neat anti-HIV toolkit. An HIV mop.

That's really clever.

I finally read about quasi-species, but I don't understand why researchers can't collect samples from lots of people, sequence the virus genomes to characterize the variations that exist, and then make vaccines for a subset of those viruses spread across the quasi-species. Then if people with the vaccine still get infected, collect samples of the virus from them, and do the same thing to find what's slipping through the cracks.

You are likely on top of this one already, but I thought you would be interested in this: using protein shells to neutralize HIV protease.

By justawriter (not verified) on 04 Feb 2011 #permalink