Oct 2, 2013
Oct 2, 2013
Oct 2, 2013
Oct 2, 2013

We have genetic engineering to thank for corn that makes its own pesticides, vitamin enhanced rice and even glowing beagle puppies. Now, a cure for AIDS may be next on the list.

Researchers at UT and Stanford University have created immune cells that are resistant to infection by HIV, the virus that causes AIDS, by using “molecular scissors” to cut apart an HIV receptor gene and fill the gap with three genes resistant to the virus.

Their research was published in Molecular Therapy earlier this month.

Inserting multiple genes, instead of one, is necessary to stay a step ahead of the
constantly mutating HIV virus, said Richard Voit, a medical and doctorate degree candidate at the UT Southwestern Medical Center who contributed to the research as a graduate student at Stanford.

“HIV is a virus that is constantly giving itself a genetic makeover, trying to hide from
treatment we throw at it,” Voit said. “That is why the current therapy involves combinations of multiple pills at the same time.”

Voit described the research as a genetic version of this “drug cocktail.”

The “gene cocktail,” so to speak, is made up of three distinct genes—including a
modified human immune gene and human/rhesus monkey hybrid gene—that code
for proteins that disrupt HIV replication. The third gene is a reengineered HIV gene
that works against its mother virus by jamming receptors needed for viral particle

To add a fourth layer of infection resistance, the three genes were specifically placed
to disrupt genes that code for a T cell surface receptor called CCR5 that a major type
of HIV uses as a point of entry.

“To infect T cells, HIV needs to get into T cells,” Voit said. “ So what we were able to
do was disrupt a protein on the surface of the cells that allows HIV to enter the cells.
It’s locking the front door of your house to prevent thieves from getting in.”

Simply disrupting the CCR5 receptor without adding the three additional genes
provided a 16-fold resistance to HIV that enters through the receptor, however, it
did not affect the infection ability of CXCR4 HIV, which uses a different receptor to
infect cells. But the best resistance against infection was seen in T cells that had the
CCR5 receptor disrupted with the three genes. The cells had more than a 12,00 fold
increase in protection against CCR5 HIV and a greater than 17,000 fold protection
against CXCR4 HIV.

In addition, being able to insert genes into an exact spot among the three
billion nucleotides that make up the human genome is a technique vital for the
development of clinical treatments using gene therapy, Voit said. Random insertion
can disrupt other important genes and swiftly turn a treatment meant to cure into a

“[Random gene insertion] can kill the cell, or worse, it can change the expression
of the DNA in such a way that it can lead to cancer,” Voit said. “ By using these
molecular scissors and targeting genes in very particular places in the genome it
drastically reduces the reliance on random integration.”

Some people naturally have mutations in the CCR5 receptor gene, the location
where the three genes are inserted, Voit said, with no apparent negative affects.

“These people are totally healthy,” Voit said. “The only difference between these people and everybody else is that they can’t get infected by HIV.”

In the future, precisely inserting this triad of HIV resistant genes into the T cells or
T cell-creating stem cells of HIV positive people and reintroducing a population of
these genetically engineered cells back into their bodies could help these individuals
have enough HIV resistant immune cells to stave off complete immune system
collapse—the hallmark of AIDS.

“It will allow these T cells to coexist with HIV in the blood stream,” Voit said. “ It is
not a cure for HIV, but what we are looking at is a potential cure for AIDS.”

There is plenty of work to be done on the lab bench before clinical trials can
be pursued, Sara Sawyer, an assistant professor of molecular genetics and
microbiology at UT and a study co-author, said. The technique needs to be attempted in
T cells from HIV positive people, and animals, but Sawyer is optimistic about the
potential of gene therapy in HIV treatment.

“Hopefully either our method or someone else’s will hit the jackpot,” Sawyer said.
“That’s all I really care about, that people with HIV can live a longer and better life,
and we can limit the spread to uninfected people.”

Looking at a list of recent gene therapy developments including the first commercially approved treatment late last year, the future seems bright.

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