The coming months may see the first
human trial of a completely new approach to treating
HIV, one which aims to give patients a brand new set
of infection-resistant blood cells. Researchers at Beckman
Research Institute of the City of Hope in Duarte, California,
have applied to the FDA for permission to begin a trial
of a gene therapy technique they call a "triple vector".
The treatment builds cells with three molecular lines
of defence against infection of CD4+ cells, according
to team leader Dr John Rossi.
Advances in antiretroviral therapy
have already made great strides in thwarting the progression
of HIV infection to full-blown AIDS. Synergistic drug
combinations create multiple obstacles to HIV replication,
and if a mutation arises that conveys resistance to
one of the drugs, the others continue to suppress reproduction.
But this new experimental gene therapy approach would
prevent the virus from taking hold on three separate
fronts.
THREE
TIMES' A CHARM
The researchers will construct a strand of DNA, encoded
to manufacture three RNA molecules that can either block
or kill HIV. That genetic material is delivered to the
body's immune cells by a harmless lentivirus vector.
To get the construct into as many cells as possible,
the team will extract stem cells from the patient's
blood — which are capable of maturing into any
type of lymphocyte — and load them up with the
vector. Though small in number, the stem cells will
survive where other lymphocytes do not.
Once in, the introduced DNA is
transcribed into three types of RNA. The first is a
ribozyme, which blocks production of a vital surface
receptor protein called CCR5. This is normally HIV's
doorway to gain entrance to the cell. Without it, the
virus should have no way in.
Others have attempted to use gene
therapy to shut the door on HIV. But they relied on
mutating the CCR5 surface receptor, rather than simply
switching it off. The genetic material that was used
to do that could conceivably trigger cancer if it spliced
into the wrong place.
If the virus somehow finds a way
around this obstacle, a second line of defence is waiting
for it in the cell wall. This hairpin-shaped molecule
intercepts the virus before it can weasel its way into
the cell nucleus and kills it by splicing itself into
the virus' own DNA.
Should this guardian molecule also
fail in its task, the last line of defence is found
within the nucleus itself. A 'decoy' RNA molecule will
be there, waiting to latch onto the viral protein known
as tat, which regulates the production of viral proteins
in an infected cell. Interrupting this process prevents
viral replication, and thus infection of new cells.
NEW
HANDS ON DECK
The researchers believe that this approach will lead
to a whole new population of immune cells that are themselves
immune to HIV. The uninfected modified cells will produce
descendants with the same genetic characteristics, eventually
shutting the virus out completely.
So, in theory, a patient who has
already been infected with HIV can develop a population
of CD4+ cells that can't be attacked by the virus, preventing
or even reversing the transition to full-blown AIDS.
Such a patient would still be HIV-positive, however,
and capable of spreading the disease to others.
The team hopes to test the therapy
initially in five patients with AIDS-related lymphoma.
But ultimately, it could be used in anyone with AIDS
or falling CD4+ counts, and could also be combined with
existing antiretroviral triple therapy.
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