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Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) have discovered a devious strategy used by the human immunodeficiency virus (HIV) to undermine the immune system.
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 signaling 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 signalling.
"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 says.
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 replication.
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.
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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