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:
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.
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).