HIV attaches to two receptor molecules on the surface of a human immune cell. ©George Eade

HIV attaches to the cell Like computer code, viruses can't do much by themselves. While computer code needs to get into a microprocessor, viruses need to get into a living cell. Then, and only then, can viruses do their dirty work of subverting cell machinery for their own purposes. How does HIV, the AIDS virus, get inside the T-cells it targets in the immune system? For many years scientists have known that the virus uses a receptor (defined) called CD4 on the outer membrane of T-cells. It's inside T-cells (and perhaps a few other cell types) that HIV reproduces. HIV eventually kills the T-cells. Since they are major players in immune response, this action accounts for HIV's eventual destruction of the immune system. Once the immune defenses are down, opportunistic infections (defined) eventually kill the patient. But there was something fishy -- CD4 seemed necessary, but not sufficient for allowing HIV inside the T-cells. The CD4 receptor was not a lone villain. In December, 1995, researcher Fiorenza Cocchi and colleagues in the laboratory of Robert Gallo at the National Cancer Institute published an article that loosed a torrent of research (see "Identification of RANTES..." in the bibliography). The report identified certain chemicals in serum (the cell-less portion of blood) that prevented cells in a lab dish from being infected by HIV. The chemicals turned out to be cellular messenger called chemokines -- chemical attractants that bring white blood cells to sites of inflammation where they can kill invading microbes. Chemokines may also be involved in auto-immune disease like lupus or arthritis, notes Gallo, one of the discoverers of HIV and a pioneer in AIDS research. Floodgates: wide The discovery of a protective factor for HIV stunned the AIDS community. In a frenzy of effort, five research groups reported last June that they'd found a receptor for chemokines. This receptor apparently helped CD4 usher HIV into T-cells. Since the new molecule worked with CD4, they called it a "co-receptor" and gave it the shorthand name CCR5. Receptors operate throughout the biological kingdom as mechanisms for passing signals through cell membranes. They are usually explained as a lock-and-key mechanism: the chemokine is the key, and the receptor is the lock. To enter a cell, HIV apparently needs to open two locks, either at once or in succession. Not just in the test tube... Researchers have found other evidence about the importance of the chemokine receptor. In fact, chemokines apparently explain some of the most intriguing data from the epidemic -- that some lucky people, despite repeated exposure, did not get infected. And that some infected people -- the so-called "non-progressors" -- do not go on to get AIDS.

			About 10 years ago, researchers found that a mysterious factor released by certain cells could block HIV, but they never succeeded in tracking it down. It was probably a chemokine.
			A 1996 genetic analysis of 1955 people in six AIDS studies showed that non-progressors and people who had been repeatedly exposed to HIV -- but never infected -- had a genetic "defect" associated with the CCR-5 receptor (see "Genetic Restriction... " in the bibliography). Pretty desirable defect. So desirable, in fact, that it could be a surviving relic of some ancient infection of HIV. Such genetic defects seem to be inherited because they confer an advantage to their possessors (see "Seeking Reasons for Disease Genes" in the bibliography).
			Daniel Zagury, a French researcher, has found that hemophiliacs (defined) who resisted infection (despite taking contaminated blood products for many years) produced high levels of the beneficial chemokines.

All these results reinforced the conclusion that the chemokine receptor indeed serves as a gateway for HIV. The true significance of the chemokine research is that the fact that HIV could enter a cell has been converted into a detailed understanding of how it enters. Says Timothy Springer, professor of immunology at Harvard Medical School, "Before this... nobody really had any way of relating this to a basic mechanism -- a molecule, a co-receptor. Now we can frame all of the really big questions about what happens in the disease process in terms of what happens to specific molecules." Gallo says that at this point, it looks like at least three chemokines, carrying the monikers RANTES, MIP 1 alpha and MIP 1 beta, "specifically block HIV-1, HIV-2 and SIV (defined) at levels of nanograms per milliliter. They're powerful suppressers of HIV. They are the most significant, naturally occurring anti-HIV suppressive factors" known. But that's not the end of it. Could chemokines actually prevent HIV infection?

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