AIDS TREATMENT NEWS Issue #299, July 17, 1998
John S. James

I. Fusion inhibitors. The CD4 molecule on the surface of certain cells (such as the T-helper cell) is often thought of as the receptor which allows HIV to enter the cell. But Dr. Gallo views the chemokine receptors (CCR5, CXCR4, and some others) as the real target of the virus. The CD4 receptor is usually necessary as well; it interacts with gp-120, a protein on HIV, to expose gp-41, another HIV protein, allowing a small part of gp-41 to penetrate the cell wall and cause fusion of the cell and viral membranes. Dr. Gallo cited recent publication of X-ray crystallography research which has given the most detailed picture yet of the of the virus- cell interaction (for a non-technical description, see "Scientists Take First Picture of AIDS Virus Attacking Cell" by Nicholas Wade, THE NEW YORK TIMES June 18, 1998, page 1 of the national edition).

This complex process of cell fusion may offer many potential targets for drugs. Dr. Gallo cited T-20, being developed by Trimeris, Inc., as a potential treatment based on this approach which is already in clinical trials, and noted that viral load drops faster than with most other antiretrovirals. [Note: For background on T-20, see AIDS TREATMENT NEWS #293, April 17, 1998.]

II. Chemokines. Dr. Gallo discussed three chemokines (rantes, MIP-1 alpha, and MIP-1 beta) which interact with the receptors CCR5 or CXCR4. There are both theoretical and epidemiological reasons to believe that these chemokines have antiretroviral effects; for an example of the latter, persons who have been exposed to HIV many times but remain uninfected have been found to have unusually high levels of these substances. But using the chemokines themselves as therapy could be problematic, due to their normal function of cell signaling; they usually provide a pro-inflammatory signal, which may not be wanted, and which might stimulate increased HIV production. For this reason some researchers have discounted chemokines as potential therapy. But Dr. Gallo pointed out that the cell signaling and the antiretroviral action are two different effects--and chemical variants of the natural chemokines can inhibit HIV infection without causing the cell signaling. These chemokine variants could potentially provide a new class of antiretroviral treatments.

III. Antibodies against tat and alpha interferon. Dr. Gallo believes (as do most HIV researchers) that HIV kills some T- cells directly--but that the larger loss is because even the uninfected T-cells do not proliferate properly. Dr. Gallo believes that part of the problem with the uninfected cells is caused by overproduction of alpha interferon (a natural inhibitor of cell proliferation) in HIV disease. Another cause of the abnormal lack of proliferation of uninfected cells may be the tat protein, which is produced by HIV and may have various harmful effects; Dr. Gallo cited recent evidence that high levels of antibodies against tat correlate with patients doing better. Also, in laboratory tests, removing tat and excessive alpha interferon from cell cultures can restore T-cell proliferation to normal.

A way to develop a treatment based on this mechanism would be to make a vaccine which would cause the body to produce antibodies against tat and against alpha interferon (to reduce the alpha interferon level to normal--and to reduce the level of tat as much as possible, since it has no normal function in the body). The vaccine would contain chemical variants of tat and of alpha interferon, designed to cause antibody production. Such a vaccine might be given several times a year--perhaps also with HIV antigen (to stimulate an HIV-specific T-helper response) to keep the virus under control. Dr. Gallo noted that the cost of such a treatment could be low enough to allow widespread use in developing countries.

Note: Dr. Gallo's talk will be available through 1999 at http://www.webcast.aids98.org. The talk, titled "How HIV Functions, Multiplies, and Causes Disease: Possible New Approaches to Therapy," is within the plenary, "Biomedical Advances in HIV Research," Thursday July 2. For those who prefer to purchase an audio tape, the tape number for this plenary is PL4. See "Geneva Conference: Finding Information on the Web and Elsewhere," in this issue.

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