Stem cells edited to produce an HIV-resistant immune system (Wired UK)


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A team of haematologists has engineered
a particular white blood cell to be HIV resistant
after hacking
the genome of induced pluripotent stem cells (iPSCs).

The technique has been published in the Proceedings of the
National Academy of Sciences
and was devised by Yuet Wai Kan
of the University of California, former President of the American
Society of Haematology, and his peers.

The white blood cell the team had ideally wanted to engineer was
CD+4 T, a cell that is responsible for sending signals to other
cells in the immune system, and one that is heavily targeted by the
HIV virus. When testing for the progress of HIV in a patient,
doctors will take a CD4 cell count in a cubic millimetre of blood,
with between 500 and 1,500 cells/mm3 being within the normal range.
If it drops below around 250, it means HIV has taken hold — the
virus ravages these cells and uses them as an entry point.

HIV gains entry by attaching itself to a receptor protein on the
CD+4 T cell surface known as CCR5. If this protein could
be altered, it could potentially stop HIV entering the immune
system, however. A very small number of the population have this
alteration naturally and are partially resistant to HIV as a result
— they have two copies of a mutation that prevents HIV from
hooking on to CCR5 and thus the T cell.

In the past, researchers attempted to replicate the resistance
by simply transplanting stem cells from those with the mutation to
an individual suffering from HIV. The rarity of this working has
been demonstrated by the fact that just one individual, Timothy
Ray Brown
, has been publicly linked to the treatment and known
to be HIV free today. The Californian team hoped to go right to the
core of the problem instead, and artificially replicate the
protective CCR5 mutation. 

Kan has been working for years on a precise process for cutting
and sewing back together genetic information. His focus throughout
much of his career has been sickle cell anaemia, and in recent
years this has translated to researching mutations and how these
can be removed at the iPSC stage, as they are differentiated into
hematopoietic cells. He writes on his university web page: “The
future goal to treatment is to take skin cells from patients,
differentiate them into iPS cells, correct the mutations by
homologous recombination, and differentiate into the hematopoietic
cells and re-infuse them into the patients. Since the cells
originate from the patients, there would not be immuno-rejection.”
No biggie.

This concept has now effectively been translated to the study of
HIV and the CD+4 T cell. 

Kan and his team used a system known as CRISPR-Cas9 to edit the
genes of the iPSCs. It uses Cas9, a protein derived from bacteria,
to introduce a double strand break somewhere at the genome, where
part of the virus is then incorporated into the genome to act as a
warning signal to other cells. An MIT team has already used
the technique
to correct a human disease-related mutation in
mice.

When Kan and his team used the technique they ended up creating
HIV resistant white blood cells, but they were not CD+4 T-cells.
They are now speculating that rather than aiming to generate this
particular white blood cell with inbuilt resistance, future
research instead look at creating HIV resistant stem cells that
will become all types of white blood cells in the body.

Of course, with this kind of therapy the risk is different and
unexpected mutations could occur. In an ideal world, doctors will
not want to be giving constant cell transplants, but generating an
entirely new type of HIV resistant cells throughout the body
carries its own risks and will need stringent evaluation if it
comes at all close to being proven.

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The team also used another technique to make the alterations to
the genes. This resulted in resistance in CD+4 T-cells, with levels
of the virus being reduced. However, further T-cell transplants
were shown to be needed to maintain this. This result in itself is
quite astounding, but not the cure Kan is working for.

10 June 2014 | 3:56 pm – Source: wired.co.uk
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