The scientists found that even when HIV does not enter a cell,
proteins in the outer envelope of the virus can bind to a molecule
called CCR5 on the cell's surface and initiate a biochemical cascade
that sends a signal to the cell's interior. This signalling process may
activate the cell, making it more vulnerable to HIV infection. It also
may cause cells to migrate to sites of HIV replication, thereby
increasing their vulnerability to infection. If the cell is already
infected with HIV, activation may boost its production of the virus.
Drew Weissman, M.D., Ph.D., formerly of the NIAID
Laboratory of Immunoregulation (LIR) and now an assistant professor
at the University of Pennsylvania; Ronald L. Rabin, M.D., of the NIAID
Laboratory of Clinical Investigation; Anthony S. Fauci, M.D., NIAID
director and LIR chief; and their colleagues report the new findings in
the Oct. 30, 1997 issue of the journal Nature.
"These new data add to our understanding of the complex
ways HIV causes disease," says Dr. Fauci. "It is a truly formidable
foe with many tricks up its sleeve." Adds Dr. Weissman, "Our
findings suggest that HIV, even without infecting a cell, can
profoundly influence the disease process by activating cells and
influencing their movement and aggregation."
HIV generally requires two receptors to enter a target cell:
CD4, and either CCR5 or CXCR4, depending on the strain of virus.
The strains of HIV most commonly seen early in HIV disease, known
as macrophage-tropic (M-tropic) viruses, use CD4 and CCR5 for cell
entry. Many strains of the simian immunodeficiency virus (SIV), a
cousin of HIV that infects non-human primates such as monkeys, also
use these receptors for cellular entry.
As described in the Nature report, the researchers found that
envelope proteins from four different M-tropic HIV strains and one
M-tropic SIV strain induced a signal through CCR5 that caused cells to
migrate in culture. In contrast, envelope proteins from other strains
of the viruses, known as T-cell tropic (T-tropic) strains, did not cause
"HIV disease is characterized by persistent immune activation,
and envelope protein-mediated signalling through CCR5 may
contribute directly or indirectly to this heightened state of
activation, with negative consequences for the HIV-infected person," Dr. Fauci
Not only are HIV replication and spread more efficient in
activated cells, but chronic immune activation during HIV disease may
result in a massive stimulation of a person's B cells, impairing the
ability of these cells to make antibodies against other pathogens.
Chronic immune activation also can result in a form of cellular suicide
known as apoptosis, and in the increased production of signalling
molecules called cytokines that can themselves increase HIV
Co-authors of Drs. Fauci, Weissman and Rabin include James
Arthos, Ph.D., Andrea Rubbert, M.D., Mark Dybul, M.D., Ruth
Swofford, Sundararajan Venkatesan, M.D., and Joshua M. Farber,
M.D., all of NIAID.
NIAID is a component of the National Institutes of Health
(NIH). NIAID conducts and supports research to prevent, diagnose
and treat illnesses such as AIDS and other sexually transmitted
diseases, malaria, tuberculosis, asthma and allergies. NIH is an
agency of the U.S. Department of Health and Human Services.
Reference: Weissman D, et al. Macrophage-tropic HIV and SIV
envelope proteins induce a signal through the CCR5 chemokine
receptor. Nature 1997;389:981-5.
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