Researchers Uncover How HIV Causes Abnormalities In Antibody-Producing
Cells
by John Bulloch
365Gay.com Health
Posted: September 7, 2004 8:31 pm ET
(New York City) HIV wreaks much of its damage by targeting the
“orchestra conductor” of the immune system, a key class of T cells —
CD4+ T cells — whose destructive relationship with HIV has been
well-studied by AIDS researchers.
More poorly understood has been the effect of HIV on another key class
of immune cells, antibody-producing B cells.
The malfunction of B cells in HIV-infected patients was first
described more than 20 years ago by H. Clifford Lane, M.D., Anthony S.
Fauci, M.D., and colleagues at the National Institute of Allergy and
Infectious Diseases (NIAID) of the National Institutes of Health
(NIH).
Now, writing in the Sept. 7 online edition of The Journal of
Experimental Medicine, Dr. Fauci, Susan Moir, Ph.D., Angela Malaspina,
Ph.D., and their colleagues identify a number of pathways that HIV
activates to damage or destroy B cells.
“Our findings further illuminate the insidious nature of HIV,” notes
Dr. Moir, head of the B Cell HIV Unit in the Immunopathogenesis
Section of the NIAID Laboratory of Immunoregulation (LIR). “The virus
has numerous ways of paralyzing or destroying the very cells of the
immune system that are supposed to eliminate it.”
One of the most paradoxical properties of HIV is the fact that it
activates the immune system, which is necessary for an appropriate
immune response, at the same time that the activation itself leads to
deleterious effects.
“During the course of HIV infection, the B cells of people whose virus
is not kept under control with antiretroviral drugs become
progressively dysfunctional through virus-driven, aberrant
activation,” explains Dr. Fauci, who is NIAID director and LIR chief.
These abnormal B cells exhibit visible changes in their structure and
surface. They also overproduce nonessential antibodies, fail to
respond properly to normal immune system signals, and have an
increased chance of dying through apoptosis, a process also called
“programmed cell death.”
In their experiments, Drs. Fauci and Moir and their LIR colleagues, in
collaboration with scientists from Human Genome Sciences (Rockville,
MD), set out to uncover what drives B-cell abnormalities in HIV
infection.
Using gene chip technology developed by Human Genome Sciences, they
probed thousands of genes taken from B cells of HIV-infected patients.
The researchers compared which genes were “turned on,” or expressed,
in the patients whose viral burden was high with profiles of gene
expression in patients whose virus was controlled by antiretroviral
therapy. The research team also examined gene expression in healthy
HIV-negative individuals.
“We found more than 40 genes that were ‘over-expressed’ in the group
with high HIV levels compared with the two other groups,” says Dr.
Moir. Most of these genes, she notes, belong to either one of two
major physiologic pathways. Of note, in patients with HIV levels,
certain elements from both pathways helped prime B cells for
apoptosis.
The researchers not only discovered new pathways that are perturbed
during the course of HIV infection, but also illuminated how HIV
affects a key B-cell survival system.
The principal player in this survival system, B Lymphocyte Stimulator
(BLyS), was discovered by Human Genome Sciences. The discovery was
first reported in a scientific journal in 1999. BLyS (also known as
BAFF) and BAFF-R — one of three known docking molecules for BLyS on B
cells — are essential for B-cell development and survival.
Dr. Moir and her team discovered that B cells of patients with high
levels of HIV have reduced levels of BAFF-R on their surfaces, making
these B cells more susceptible to cell death.
The LIR researchers plan to examine whether similar pathways are
triggered in other cells of the immune system that are over-activated
by HIV, including CD8+ T cells, CD4+ T cells and natural killer (NK)
cells.
Whether common or distinct pathways are involved, these new findings
help explain one of the driving forces of HIV immunopathogenesis and
may lead to therapeutic strategies aimed at quelling the aberrant
levels of immune cell activation,” notes Dr. Fauci.
©365Gay.com 2004
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