Bulletin of Experimental Treatments for AIDS, No. 3, June 1989
Ron Baker

Phase II trials (for efficacy) are currently stalled at several medical centers, including San Francisco General, N.Y.U. and Stanford. These proposed trials plan to study CD4 in combination with AZT.

Dr. Mamoru Watanake and colleagues report that they injected CD4 into 4 rhesus monkeys for 50 days.

** Watanake M, et al. Effect of recombinant soluble CD4 in rhesus monkeys infected with simian immunodeficiency virus of macaques. Nature , 337(6204):267 270, January 19, 1989.

Two of the monkeys were infected with SIV (simian immunodeficiency virus), which resembles HIV and causes a similar disease. After a week of treatment with CD4, SIV could not be found in the cells of the infected monkeys. When therapy was stopped, the virus reappeared. This indicates CD4 can suppress detectable SIV. The researchers hope CD4 will produce a similar effect in HIV infected humans. Although the study suggests that CD4 may temporarily reverse the bone marrow damage caused by the SIV infection, one of the 2 infected monkeys died from severe anemia a few days after the CD4 treatment stopped.

Many researchers are enthusiastic about CD4, but there are several weaknesses and disadvantages to this therapy. First, the drug will probably require at least one daily injection if it is to be effective. Second, CD4 does not cross the blood brain barrier, and therefore may not be effective in preventing or treating HIV brain infection. Laboratory experiments by Dr. Paul Clapham and colleagues indicate CD4 can stop HIV from infecting helper cells and macrophages, but not brain and muscle cells.

** Clapham PR, et al. Soluble CD4 blocks the infection of diverse strains of HIV and SIV for cells and monocytes but not for brain and muscle cells. Nature , 337(6205):368 370, January 26, 1989.

Finally, although CD4 may be able to block HIV infection between cells, when used alone the drug cannot kill cells already infected with the virus.

As a way of possibly overcoming some of these disadvantages, scientists have developed specially designed CD4 drugs. Some of these new drugs combine CD4 with toxins that recognize and kill infected cells.

More recently, researchers at National Cancer Institute, Harvard Medical School, and Genentech, Inc. have combined CD4 with an artificial human antibody molecule. In test tube studies, this hybrid CD4 not only prevents the virus from infecting new cells but also actually seeks out and kills the virus and infected cells.

** Capon DJ, et al. Designing CD4 immunoadhesins for AIDS therapy. Nature , 337:525 531, February 9, 1989.

The CD4 hybrid also stays in the bloodstream much longer than CD4 alone. Individuals using this hybrid will probably need fewer injections per week. In tests on infected rabbits, CD4 with the artificial antibody killed infected cells and continued working in the animals' blood up to 200 times longer than the original CD4.

Other possible advantages of the hybrid CD4 are its theoretical ability to neutralize different strains of HIV and the possibility the drug can activate the immune system to attack HIV on its own.

** Ibid

The artificial antibody also locks onto the surface of infected macrophages and may signal uninfected macrophages to destroy them.

Researchers have expressed enthusiasm for the potential of CD4. But some remain cautious. "This is a technological leap," commented Dr. Samuel Broder of the NIH*. "Whether it has clinical value is something we will have to examine."
890601
BETA0305

Copyright © 1989 - Bulletin of Experimental Treatments for AIDS (BETA). Reproduced with permission. BETA is published four times a year by the San Francisco AIDS Foundation. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. Call 415.487.8060; FAX: 415.487.8069. Mailing Address: P.O. Box 426182, San Francisco, CA 94142-6182.  beta@sfaf.org  http://www.sfaf.org/beta.html