AEGiS-GMHC: Be Kind to Your Chemokines

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

Be Kind to Your Chemokines

GMHC Treatment Issues, Volume 10, Number 6/7 - June/July 1996
Dave Gilden

The rapidly increasing understanding of the way in which HIV gains access to new cells may lead to new strategies for stopping the virus. Last month saw the announcement of "fusin," a second receptor alongside the long-known CD4 receptor to which HIV needs to bind when infecting cells (see Treatment Issues, May 1996, pages 1-2). Fusin turns out to be useful only to a restricted variety of HIV strains, notably lab strains and the strains frequently appearing late in disease, which are T-cell tropic (they especially bind to and infect CD4 lymphocytes in test tube cultures). In late June (at Treatment Issues' press time), no less than five papers appeared in three journals (the June 20 edition of Nature and the June 28 editions of Science and Cell) claiming that a related receptor is the co-receptor for the so-called macrophage-tropic HIV strains present earlier in the disease process. This new receptor is designated chemokine receptor 5, or CC-CKR-5.

CC-CKR-5 normally binds to a class of intercellular messenger molecules called "b-chemokines." The major known function of chemokines is to attract immune cells to sites of infection, but several, RANTES, MIP-1a and MIP-1b, also interfere with HIV replication, according to recent discoveries made by Robert Gallo's lab at the National Cancer Institute (see Treatment Issues, January 1996, pages 10-12). It turns out that CC-CKR-5 is a common receptor for all three of these chemokines. In the experiments described by the five articles, HIV was able to infect cells bearing both the CD4 and CC-CKR-5 receptors, but not just CD4. That infectability was practically eliminated in the joint presence of RANTES and the two MIPs. When only one of these chemokines was present, infectability was greatly reduced but not eliminated.

The simplest explanation seems to be that by binding to CC- CKR-5, the chemokines block HIV from joining with cell membranes and entering the cells. One research group, from the Aaron Diamond AIDS Research Center in New York, also looked at two "exposed but uninfected" individuals, i.e., persons who have remained HIV-negative despite a lifestyle that almost certainly exposed them to the virus. Lo and behold, CD4 cells from these two individuals were not only were exceptionally resistant to intrusion by HIV. They also produced abnormally high amounts of the RANTES and MIP-1a and b. The researchers have not yet determined whether this overexpression of chemokines or some genetic defect in CC- CKR-5 is at the root of the cells' resistance to HIV.

Should the chemokines prove to be the key to protecting cells from HIV, it is probably not a good idea to just inject large quantities of these molecules into patients' bloodstreams. High levels of the b-chemokines are associated with several autoimmune diseases. Still, it should be possible to develop benign drugs that bind to either part of CC-CKR-5 or, more likely, to the part of HIV's gp120 envelope protein that attaches itself to this receptor. As Treatment Issues reported last month when discussing fusin, such drugs might already exist among the various known compounds (some already under development as drugs) that block HIV's entry into new cells.

But there are limits to such an anti-CC-CKR-5 binding strategy: the cells that the Aaron Diamond group isolated from the two exposed but uninfected persons were susceptible to infection by HIV that depends on fusin rather than CC-CKR- 5. More generally in the experiments, the specific characteristics of the envelope protein on different HIV strains affected the strains' sensitivity to b-chemokines, and characteristics of different cell types also seemed to have a major influence. Researchers at Harvard are proposing two additional chemokine receptors, CKR-3 and CKR-2b, as alternatives to CC-CKR-5 or fusin in certain cells. Whether or not this is confirmed, drugs that might help some people might not help others or might only protect some types of cells.

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