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Short-Circuiting HIV Replication

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Tadeys:
In the Jan. 21 early edition of the Proceedings of the National Academy of Sciences, investigators reported that they have discovered an exploitable mechanism to rid the body of HIV.

Current antiretroviral drugs effectively suppress the virus, explains James Stivers, Ph.D., a professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine's Institute for Basic Biomedical Sciences, and colleagues at University of California, San Diego and the University of Utah School of Medicine, but they don't get at copies of the virus lurking in the DNA of in nondividing cells. "And," he says, "the minute you stop taking antiretrovirals, it starts replicating again."

HIV, like other viruses with RNA genomes, makes a DNA copy of itself in its target cells, integrating itself into the cell's DNA, then relying on certain cellular components to reproduce. But cellular DNA replication, an error-prone process, depends on multiple control mechanisms to rid replicating DNA of incorrect bases that become inserted in the process. For example, many DNA polymerases cannot discriminate between dUTP found in RNAs and dTTP, which is restricted to DNA, mistakenly putting a uracil in the nascent DNA chain where there should be a thymine.

To control dUTP levels, says Dr. Stivers, most human cell types have an enzyme that breaks down dUTP, uracil DNA glycosylase (dUTPase). As another fail-safe measure, the enzyme hUNG2 snips stray uracils out of newly copied DNA strands, leaving the resulting holes to be filled by a different repair enzyme. Certain resting cells targeted by the virus lack the first quality-control mechanism because, Stivers explains, "They're not replicating their DNA and dividing, so they couldn't care less if they have a lot of dUTP."

When a retrovirus like HIV invades a cell, it immediately makes DNA copies of its own RNA genome, then inserts them into the host cell genome. If there are many dUTPs floating around, they wind up in the new viral DNA, and, potentially, are removed by hUNG2. The question, Stivers said, left open by the conflicting results of previous studies, was what effect, if any, this process has on HIV and similar viruses.

The investigators found, in measuring dUTP levels and hUNG2 activity in human cells grown in vitro then exposed to HIV, that cells with high dUTP but little hUNG2 activity were highly susceptible to the virus, as were cells with low dUTP levels but high hUNG2. In cells with high UNG2 levels, the enzyme would snip out the few stray Us, but the resulting holes would be repaired, leaving the viral DNA as "good as new."

But in cells with both high dUTP and vigilant hUNG2, Dr. Stivers said, the repair process left the viral DNA so riddled with holes that it was beyond repair. "It's like dropping a nuclear bomb on the viral genome," he said.

Stivers noted that dUTP may turn out to be a "potentially interesting pharmacologic target against HIV-1." Further, a protein expressed by HIV degrades UNG in some immune cells, he explains. Unable to repair damaged DNA, these cells are then more prone to infection. If researchers designed a drug that blocks the interaction between the HIV protein and UNG, they might be able to protect the immune cells from infection, he said.

http://www.genengnews.com/gen-news-highlights/short-circuiting-hiv-replication/81247886/

OneTampa:
Is this similar to the announcement from the Stanford University School of Medicine?

http://med.stanford.edu/ism/2013/january/porteus.html

Dr.Strangelove:
No, it's something completely different.

The Stanford people have found a clever way to further improve the Sangamo approach. In their current approach Sangamo draws blood from a patient, seperated the CD4 cells and infuses them with a designed zinc-finger-nuclease that can specifically bind to the gene of the CCR5 receptor. A small piece of that gene is cut out and therefore no functional receptor can be produced by that CD4 cell anymore. Then the immunized cells are infused back into the blood stream of the patient.
While the CCR5 receptor of CD4 cells is the main entry gate for HIV into the human body, it is not the only one. The Stanford researchers have added an additional step. Instead of just cutting out a piece of the CCR5 gene and thus deactivating it, they add three additional genes in that place. The proteins that are expressed by those genes further protect the cell from HIV.

Now, the PNAS paper of the John Hopkins researchers is a whole different thing. I'm rather skeptic about that one for several reasons. I would be surprised if this ever makes it into any form of HIV treatment or prevention.

Mishma:
I knew folks that were doing gene knockins while I was doing gene knockouts to study genes and their regulation. Usually we both added or deleted several (1-100) base pairs so as to render the homologous recombined "gene," non functional (aka knockout) or hyperfunctional (HIV steals one of our important immunoregulatory elements, transcription factor NFkb, in its reading frame.) aka knockins. I'm surprised that these "stacks" are even functional. More than just linear base pairs though, as DNA's 3 dimensional feature is also a compounding variable and adding or removing 3 genes and knocking one out (zinc finger) could very well change its structure. Throw in the epigenetics and......... We'll need replication and years to know more. Indeed this is promising. 

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