A controversial marrow transplant operation in the US, a faulty gene in a dormant strain of the HIV isolated in Australia, the Zinc Finger factor ... the AIDS war is not lost yet, says SUNITA RAINA
Two hoots to AIDS
THE scene could be straight out of a
medical sci-fi a baboon is sacrificed and
its bone marrow processed; a person
terminally ill - an AIDS (Acquired
Immuno Deficiency Syndrome) victim
who has volunteered to be a human
guinea pig - is infused with about a
pint of straw-coloured fluid containing
baboon cells, which then flows from a
plastic bag hung at the bedside, into a
vein in the man's arm. The aim is to
construct a parallel monkey-derived
immune system in the man with in
impaired immune response.
Yet, this was no medical fiction. The
scene of this real life drama was one of
the operation theatres in San Francisco
General Hospital, USA. Meanwhile, there
raged a stormy debate. The doctors concluding this highly risky operation were
being castigated for violating medical
ethics. The doctors had decided to go
ahead on the face of warning from science advisors at the Food and Drug
Administration (FDA) that it had greater
chances of killing than benefiting the
patient. But the patient had, in fact,
campaigned for two years to be allowed
to offer his services to science. And the
controversy Would take a long time to
die down.
"This represents not scientific
progress but medicine and science gone
mad," exclaimed experts in disgust.
Chemotherapy, radiation and baboon
cells involved in the transplant are likely
to intensity the victim's infection by further weakening his damaged immune
system, they held.
Prior to the bone marrow transplant, the patient underwent drug and
radiation treatment to destroy virtually
all of his already damaged immune system to prevent rejection of the transplant by the body. These exercises
meant that the patient would surely die
of AIDs-associated infections if the transplant failed.
"I know I could die from this treatment. But I am certain that I will die if I
do nothing," said Jeff Getty, the test
subject. He said that there are few treatments open to a late-Stage AIDS sufferer
like him and he was putting his life on
the line "to try to get some answers".
Nevertheless, scientists and medical
ethicists have something else to say.
They strongly feel that the test has slim
possibility of helping AIDS Victims, on
the contrary, scientists fear that the
baboon transplant might carry known
and unknown microbes that could go
on to unleash a new epidemic like AIDS.
But Getty and his doctors went
ahead with the experiment, nevertheless. The underlying principle of this
novel experiment is deceptively simple,
Baboons are resistant to AIDS virus. If
everything goes as planned, the baboon
cells injected into the patient's body will
ride through his circulatory system to
settle in his bone marrow. Once the
baboon's immune cells take hold in
Getty's body, they will perform the job
that his AIDS-devastated immune system
cannot.
The baboon marrow was processed to contain only two types of cells -
stem cells that mature into key components of the immune system, and facilitator cells that allow stem cells to proliferate in other species without producing the fatal reaction called graft-versus-
host reaction.
'
If successful, the experiment shall
boost animal-to-human transplants,
known as xenotransplantation. The
field is currently undergoing a revival of
interest due to shortage of human
organs and advances in immunology.
There are critics, like Martin Stephers of
the Humane Society in the US, who condemns xenotransplantation since "it
does not balance the risk to the animal
and the potential reward to humanity".
it is feared that one such success, like
this experiment, could open up the
floodgates for a much gloomier scenario
of assembly-line transplantation from
animals to humans.
Apart from this controversial test, fight
at the AIDS front in recent months has
been greatly encouraging. Advances,
though halting, reassure that AIDS might
not be invincible after all- A major
breakthrough was achieved when an
Australian team cracked a mystery - a
group of people who had contracted
AIDS virus through transfusion 14 years
ago, but were still healthy, all due to a
faulty gene in the strain of virus which
infected them.
"Not only have the recipients and
the donor not progressed to disease for
15 years, the prediction is that they
never will," marvels Australian molecular biologist Nicholas Deacon. "What
these results suggest is that the human
immuno deficiency virus (HIV) is vulnerable and that it is possible to stimulate effective immunity against it," says
Barney Graham of Tennessee's
Vanderbilt University in Australia.
Due to the presence of a defect in a
gene - known as NEF, for negative factor, the virus is able to form very few
copies of itself inside T cells, the
immune system cells that the virus targets. Subsequently, a strong defence
mounted by the immune system keeps
the virus under control for many years.
Scientists feel that the immune response
launched thus may help prevent infection by more virulent strains of the AIDS
virus.
This makes the NEF gene a promising
target for drug developers. "If its activity can be blocked, researchers might be
able to hold the progression of disease at
bay, even in people who have developed
full-blown AIDS," suggests Deacon. This
bears significance in light of the fact that
the powerful new generation Of AIDS
drugs, called protease inhibitors, have
sparked a debate vis-a-vis its efficacy.
Some medical analysts are sceptical
about the long-term value of this class
of drugs, noting that the virus causing
AIDS tends to mutate quickly. While the
FDA approved two drugs in this class
recently, named Saqumavir and
Retanivar, it was unanimously felt that
such drugs may need to be used in combination with other therapies.
The most coveted goal of AIDS drug
research remains a hunt for the drug
that solves the problem of drug resistance, while actually eliminating HIV
from the body. Scientists made two significant advances in this direction in
recent months. Since HIV mutates very
fast, strains that resist a drug's toxic
effects can evolve quickly. The immediate aim was to abort designs of the virus
to develop drug resistance. Scientists
recently celebrated the discovery of a
family of drugs that do not allow evolution of drug-resistant mutant strains of
viruses, including HIV.
By attacking the inner core of HIV
called the Zinc Finger, Disulphide-substituted Benzamides (DIBAS) disable the
virus to multiply. Zinc Finger is a protein containing a molecule of zinc that
maintains a three dimensional structure
of the virus. They have to stay the same
if the virus has to multiply. DIBAS are
found to remove zinc from the fingers
disabling the virus (Down To Earth,
Vol 4, No 16).
Researchers feel that this family of
drugs may be a useful addition to the
drug cocktail that might hold HIV in
check indefinitely. "If Zinc Finger agents
turn out to be as patent as these early
experiments show, they might be very
useful if we combine these with other
drugs," says Clive Loveday, a virologist
at Middlesex Hospital in London.
In addition, the first hints that it
may be possible to eliminate HIV if the
drug is given soon after the initial exposure sent the spirits of researchers seating. Since most HIV victims do not know
exactly when they became infected, the
discovery might at least save healthcare
workers who fall in the clutches of the
killer, accidentally.
A drug called PMPA was found to
remove all traces of the simian immunodeficiency virus (SIV), which causes a
disease Similar to AIDS in macaques. It
was discovered that PMPA stays longer
inside cells than zidovudine or AZT, the
leading AIDS drug. Thus, it gets more
time to combat the virus, eventually
eliminating it completely. "It is some
thing we have observed though we don't
know why it happens," says Che-Chung
Tsai at the University of Washington in
Seattle. The snag remains that the drug
has to be administered immediately
after the virus gains entry into the body.
In fact, what scientists really want is a
vaccine that call prevent infection altogether. That is what makes the virus
strain discovered in Australia so
promising, and controversial also.
Could a weakened strain of the HIS,
stripped of the NET gene, make development of the vaccine possible?
Ronald Desrosiers at the New
England Regional Primate Research
Centre provides hope. Ongoing work
oil SIV has indicated that "when the NEF
gene is removed from SIV, the virus has
no longer the power to make monkeys
sick. Moreover, monkeys inoculated
with the NEF-free SIV developed marked
resistance to the more virulent strain",
recounts Desrosiers.
But testing a vaccine with live Irv,
however weakened, on uninfected people sounds like walking over
a landmine. After all, HIV is
a retrovirus, a class of infectious agents known for their
ability to integrate their
genes into the DNA of the
cells they infect. These can
remain hidden for years,
triggering the disease when
the immune System falters.
The proposition of testing the live retroviral vaccine on perfectly healthy
individuals, thus, does not muster much support.
Nevertheless, sonic researchers do not
want to write off a retroviral
vaccine prematurely. "A live vaccine
made from HIV can be
made safer by removing
not just the NEF gene but
several others as well,"
maintains Desrosiers.
Since the safety concern is
overwhelming at present,
most AIDS researchers
argue that "the only prudent strategy is to concoct a hybrid vaccine, putting the key features of a disabled AIDS virus into something more
benign than a retrovirus; like the vaccine virus that successfully wiped Out
smallpox".
Till scientists find an answer to this
dilemma, targeting the immune system
rather than the virus seems a plausible
alternative. Using natural substances
produced by the human body to stimulate the immune system to fight the
virus has attracted immunologists for
long. The recent discovery of some such
proteins created a buzz among researchers. interlelikin-16, a complex molecule isolated from the human immune
system, was found to prevent the virus
from replicating itself. Similarly, three
chemicals - known as Ramcs, Nup I -
alpha, and mipl-beti, also seem to block
the progress of the disease.
Will these proteins in reality cure
AIDS patients? Scientists are hopeful, yet
cautious. Injecting these proteins
directly into AIDS Victims is fraught with
risks, feel researchers. "The chemicals
may have other effects on the body,
including potentially toxic effects, if
given in large amounts, 11 cautions Bruce
Walker of the AIDS Research Centre at
the Massachusetts General
Hospital, USA.
However, "from a
conceptual standpoint the
discovery is very important," says Anthony S
Fauci of the National
Institute of Allergy and
Infectious Diseases in the
us. The findings of these proteins have
opened new pathways for AIDS research.
Clues to various mysteries have been
offered. Why does the virus never take
hold in some people who are repeatedly
exposed to it through risky behaviour?
Why, even among infected people, some
live into a second decade without succumbing to the disease while others fall
ill within a few years Of HIV infection?
Above all, the action of these immune
system chemicals might solve the central mystery Of AIDS vaccine research-
what reaction by the body must a
vaccine elicit to protect against HIV
infection?
The intense reactions to various
approaches and findings reveal the
extraordinary complexities of the AIDS
research. Various strategies adopted by
us to contain this most dangerous
epidemic of the 20th century, like
drugs, vaccines and immuno modulation, need further research. After all, we
are dealing with chameleon of a virus
that constantly changes tactics to
counter our defences. But as researchers
celebrate every advance they make at
combating the deadly enemy, it
becomes clear that AIDS may be anything
but invincible.
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