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Gene focus of the new Tre enzyme?
Aug 14, 2007

Hey guys,

Hoping you can help me clarify something. Regarding the recent news of the creation of the Tre enzyme by the German scientists:

In the technical literature that you have access to is it specifically mentioned which of the "cross-mutation common" HIV proviral gene is being targeted by Tre (gag, pol, env, tat, rev, nef, vif, vpr, vpu)?

I can't get access to the specific report in Science, and there are many contradictory "layman's terms" articles with none of them giving the genetic specifics.

THANKS!

Response from Dr. Pierone

Hello, and thanks for posting.

Medical research involves two general types of activities which roughly be divided into basic science and clinical work.

Basic science is bench work in the laboratory involving the underlying biology which provides the structure of our understanding of normal physiology and disease states. Molecular biology is the study and manipulation of genetic material and much of our understanding of HIV has been generated from this discipline.

The field of molecular biology is so specialized, complex and rapidly changing that it requires a great deal time to read and learn about it. Hence, most doctors who perform clinical research (myself included) have, at best, a rudimentary understanding of what molecular biologists are describing in their research reports.

With that forewarning, I will translate what I gleaned from the article describing the Tre enzyme from the June 29th, 2007 issue of Science magazine:

As background, the HIV genome starts as RNA and after infecting a human cell is converted into DNA (via reverse transcriptase). This HIV DNA then becomes integrated into host cell DNA (via integrase) where it may lurk as a dormant reservoir for future activation and eventual production of infectious HIV particles. This latent element of the HIV lifecycle is why cure of infection has been so problematic. So what can be done about this integrated viral DNA quietly waiting in the shadows for a future ambush?

The natural next question is whether it is possible to figure out a way to remove this integrated HIV DNA from infected human cells? Based on this remarkable study, the answer is yes.

The HIV genome contains the multiple genes which you mentioned in your question (gag, pol, env, etc) and these functional genes are flanked on both sides by genetic material called LTR's for long terminal repeats. So the essential genetic blueprint for HIV is contained in between these flanking LTRs.

There are enzymes called recombinases which allow genes to be cut (and pasted) and these proteins play a crucial role in the processing of genetic material. These researchers produced a recombinase enzyme Tre which was designed to specifically recognize and cut a region in the HIV LTRs. By doing so on both ends of the LTRs it actually snips out the HIV genome from the human cell DNA. This feat was accomplished in test tube studies and provides the first proof of concept for 'gene therapy' clearance of integrated HIV from infected human cells.

So really this is a first step towards the potential cure of HIV infection, but obviously important. There are huge hurdles to overcome before this type of therapy would offer the promise of cure of HIV infection. But this landmark study will spark new questions and follow-up studies to advance towards this ultimate goal.



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