Thursday, May 20, 1999

How HIV attacks the immune system

OVER the past 15 years, governments and institutions have
poured millions of dollars into AIDS (Acquired Immune
Deficiency Syndrome) research. Researchers and doctors have
drastically improved treatments for the disease and gained new
understanding of how Human Immune Deficiency Virus (HIV), the
virus that causes AIDS, infects cells. Nevertheless,
scientists still understand relatively little about how HIV
causes the immune system to collapse, the ultimate consequence
of infection.

Most researchers have held that HIV directly kills the immune
cells called helper T cells, or CD4 cells, eventually
exhausting an immune system that is frantically making
replacements. The latest studies, however, suggest that
different pathways of CD4 cell disruption may be more
important.

Some researchers now suspect that the virus chokes off the
supply of new immune cells. Still, others are beginning to
suggest that HIV changes the signals that send immune cells
migrating through the body, directing CD4 cells away from the
blood where they normally circulate and toward sites where
they may be destroyed.

The disagreement is more than an academic issue. Understanding
how HIV triggers immune-cell depletion may eventually enable
researchers to block its devastating effects. Also, new
knowledge could reveal strategies for AIDS therapies that go
beyond the drugs that patients now take to slow replication of
HIV.

Early infection with HIV is marked by symptoms similar to
mononucleosis: fever, enlarged lymph nodes, rash, muscle aches
and headaches. Within one to three weeks, the immune system
gets some control over the virus by producing antibodies and
cells that recognize and kill some of the infected cells.

HIV reproduces itself quickly, however, and continues to
replicate throughout the course of infection. Because HIV
contains RNA and uses it as a template for DNA during
reproduction, the agent is classified as a retrovirus. Six
months or so after infection, HIV reproduction reaches a set
point, which varies from patient to patient. In this stage of
disease, a person is unlikely to notice any symptoms. However,
the higher the set point, the greater the amount of virus
carried, and the faster a person is likely to develop AIDS.

Over the next eight to 10 years, the virus slowly overwhelms
the immune system, eventually causing a catastrophic decline
in the number of CD4 cells. When the concentration of CD4
cells drops below one-quarter the normal concentration, a
person is said to have AIDS. The ensuing immune deficiency
renders the person vulnerable to the opportunistic infections
that mark the disease, such as tuberculosis and the rare
cancer known as Kaposi's sarcoma.

Exactly how HIV eludes the immune system so long and
effectively is unclear. Researchers suspect that part of the
virus' elusiveness lies in its tendency to infect the very
cells that are activated to fight off the infection. CD4
cells, the white blood cells that HIV primarily targets,
marshal responses from two other kinds of immune cells: those
that produce antibodies and those that destroy infected cells
directly.

Only a small proportion of a person's CD4 cells are typically
dividing - posing a problem for HIV. The virus can't replicate
efficiently without hitching a free ride on the protein-making
machinery of a T cell that is already reproducing. However,
when researchers began to measure how much virus infected
people typically carry, concentrations of HIV were higher than
would be expected given CD4 cells' reproduction rate.

In 1995, David D. Ho of the Aaron Diamond AIDS Research Centre
in New York and Alan S. Perelson of Los Alamos (N.M.) National
Laboratory calculated that HIV infects and destroys several
billion CD4 cells each day throughout the course of the
disease.

That rate of cell destruction would lead to AIDS more quickly
than has been observed unless the immune system increases CD4
cell production above normal, they said. While replenishing
the population, rapidly dividing CD4 cells present additional
targets for the virus.

The stresses of initiating massive production of new cells in
response to depletion of CD4 cells must be what eventually
triggers the especially marked decline in CD4 levels, asserted
Ho and Perelson. Just as an overy can only produce so many
eggs over a woman's lifetime, so can the immune system
manufacture only a certain number of new cells, they reasoned.

This model accounts for several characteristics of HIV
treatment, says Ho. These include the rapid drop in HIV
concentration and the quick rebound in CD4 cells counts
detected in blood samples after a person begins antiretroviral
therapy and the rapidity with which drug-resistant viruses
develop.

On the other hand, Ho's theory fails to account for the
observation that CD4 cells move from tissues and lymph nodes
to the blood soon after antiretroviral therapy begins. The
model also assumes that the dynamics of CD4 cell turnover are
similar in both early and late HIV infection, which may not be
the case, according to Mike McCune of the Gladstone Institute
of Virology and Immunology at the University of California,
San Francisco.

If Ho's model is correct, antiretroviral drugs, which slow the
destruction of helper T cells, reduce the need for production
of CD4 cell replacements. A study by McCune and his
colleagues, however, indicates that antiretroviral therapy
actually allows the immune system to boost its production of
new T cells above normal levels. This suggests that HIV acts,
in part, by inhibiting the production of new CD4 cells, the
scientists propose in the January edition of Nature Medicine.

If HIV blocks the production of new helper T cells, then "to
treat the disease, not only do we need potent antiretroviral
drugs to stop the virus from spreading and destroying T cells,
we may also need additional therapies to ensure that T cell
production starts anew," says McCune.

Using a new technique that biochemically labels dividing T
cells, including CD4 cells, the researchers compared the blood
of HIV-positive patients who were not yet receiving
antiretroviral drugs, HIV-positive patients who had just
completed a 12-week course of antiretroviral therapy, and
volunteers not infected with HIV.

They found much higher concentrations of new CD4 cells in the
blood of patients who had received antiretroviral therapy than
in HIV-positive patients yet to receive drugs and in
uninfected volunteers. The studies also indicated that CD4
cells actually survive longer in HIV-positive patients who had
not been given antiretroviral drugs than in patients who had
been given the drugs. These findings suggests that the net
gain in CD4 cell count during aggressive antiretroviral
therapy results from an increase in CD4 production rather than
a decrease in CD4 destruction, McCune said.

McCune's study "puts an end to four years of exciting debate"
and confirms that HIV's effect on CD4 cell production is at
least as important as its effect on CD4 cell destruction, says
Giuseppe Pantaleo of the University Hospital of Lausanne in
Switzerland. Panataleo, who has used a different technique for
estimating CD4 cell production, has likewise found that HIV
inhibits CD4 cell production.

Further confirmation of the observation that HIV limits the
production of new CD4 cells came last month from research in
the Netherlands. Scientists there isolated precursors of CD4
immune cells from blood samples of HIV-infected patients and
then cultured these cells in the laboratory to see how they
developed.

The initial blood samples were taken soon after the patients
learnt they were infected with HIV. Six months later, blood
samples taken from patients who went on to develop AIDS had
lost about 90 per cent of their ability to develop new CD4
cells compared with the initial sample, according to Frank
Miedema of the Sanquin Blood Supply Foundation in Amsterdam
and his colleagues. In contrast, blood from HIV-positive
people who had not progressed to AIDS had retained about half
of its original ability to grow new CD4 cells, he found.

This suggests that HIV blocks the ability of the immune system
to produce new CD4 cells, he said last February in Chicago at
the Sixth Conference on Retroviruses and Opportunistic
Infections.

Not everyone agrees that Ho's model of immune system
exhaustion is on the way out. A team of German researchers
reported at the same conference that among 13 HIV-positive
patients, the concentration of actively dividing CD4 cells in
their lymph nodes dropped during nine to 12 months of therapy.
This suggests that in the absence of treatment, HIV
replication in the lymph nodes causes CD4 cells to divide more
rapidly than normal, says H.J. Stellbrink of the University
Hospital, Eppendorf in Hamburg.

There's yet a third way that HIV might reduce the number of
CD4 cells in the blood. The virus might redirect many of these
cells to tissues and lymph nodes, where they may be destroyed.
A paper published in the January edition of the Journal of
Immunology supports the idea that HIV - at least in immuno
deficient mice - commandeers a natural immune process known as
homing, which causes CD4 cells to flood out of the bloodstream
and into the lymph nodes.

Immune cells, including CD4 cells, constantly patrol the body
for invaders and move along a daily route from the lymph
nodes, through tissues, into the blood, and then back to the
lymph nodes. In February 1997, virologist Miles W. Cloyd, of
the University of Texas Medical branch at Galveston and his
colleagues showed that when HIV binds to any of several types
of immune cells, including CD4, those cells produce higher
than normal amounts of a protein known as CD62L and then move
directly into the lymph nodes.

"It appears that once HIV-exposed helper cells are triggered
to leave the blood, they are programmed to self-destruct,"
says Cloyd, who noted that about half of the HIV-infected CD4
cells entering the lymph nodes were destroyed in his
experiments on mice.`

Cloyd's newly published research confirms that HIV infection
triggers the molecular homing signal. It also indicates that
after being infected with HIV and moving into the lymph nodes,
CD4 cells are more likely to die than are another type of
infected T cell called CD8 cells. Cloyd says that this finding
could explain why the number of CD8 cells does not
dramatically decline during HIV infection.

Although Cloyd's theory remains to be tested in humans, he
suggests that enhanced homing might explain several apparent
quirks of HIV infection. For instance, homing could underlie
the disappearance of immune cells from the blood and their
accumulation in lymph nodes in HIV-infected people, he says.

The theory could also explain how so many CD4 cells could die
during HIV infection although they are not actively dividing
and producing the virus. According to his model, such
HIV-infected cells may self-destruct, says Cloyd.

As research progresses, the picture of HIV infection seems to
become even more complicated. McCune suggests that none of
these models is exclusive. HIV may destroy many CD cells,
block the production of new cells, and also redirect the
movement of immune cells throughout the body. "Data gathered
during the next few years will give us a much better picture
about what is happening," he says.

So, are there any clear answers about how HIV causes the
drastic drop in CD4 counts seen in AIDS patients? "It's still
an open question," says Anthony Fauci, director of the
National Institutes of Allergy and Infectious Diseases in
Bethesda, Md.

The need for more data is pressing. "We need to understand
more and more how the (immune) system is working so that we
can develop different treatment approaches," Panbtaleo says.

     Science News Online Damaris Christensen


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