AIDS TREATMENT UPDATE, August 1995
Edward King

Professor Jay Levy from San Francisco argues that the limited effectiveness of current approaches to treating HIV infection is the result of researchers' emphasis on trying to prevent the infection of human cells by HIV viruses circulating in the body. He believes that it may be more important to find ways to attack human cells that have already been infected by the virus.

Levy points out that infected cells, particularly in the lymph nodes and other tissues, are responsible for the steady production of new virus. Some infected cells survive for long periods, churning out new HIV viruses. Current anti-HIV drugs target these newly produced viruses, reducing the number of new cells they infect, but seem to have little effect on the cells that are already infected. In other words, the drugs are attacking new viruses as they come off the production line, but doing little to stop the machinery that is manufacturing them in the first place.

Levy also argues that HIV-infected cells produce abnormal levels of cytokines or emit HIV proteins that disrupt the immune system. Moreover, it is probable that HIV is usually transmitted from person to person by the transfer of HIV-infected cells, which can survive longer in someone else's body, rather than by the transfer of free-standing virus particles.

New treatment approaches should investigate ways of boosting the parts of the immune system that attack infected cells, such as natural killer cells and CD8 lymphocytes, according to Levy.

Researchers are becoming increasingly reliant on tests that measure the amount of HIV in the blood to provide information about the course of HIV infection and the effects of anti-HIV drugs. However, these tests are almost always used to measure the amount of HIV in blood samples, whereas Levy points out the most virus production is probably occurring elsewhere in the body tissues.

Dr Clive Loveday, a virologist at University College London Medical School who is closely involved with the Medical Research Council's HIV research, told AIDS Treatment Update that he agreed with Levy's critique. "We have always known that with current approaches we are not looking directly at the virus factory, but one step removed. With new drugs, or combinations of drugs, clearly the factory itself is the best target."

CONTROVERSY

However, some researchers believe that Levy's argument may be over-simplistic.

Some scientists think that the immune damage seen in people with HIV is not caused by the virus directly killing the cells it infects. Instead, they argue that it may be possible for HIV-infected cells to survive and function properly for long periods. They believe that the main reason for the loss of CD4 T-cells in people with HIV is that HIV-infected cells are identified and destroyed by the immune system, rather than killed by the virus itself. If this is true, the best treatments might be those that specifically suppress the immune system's attack against HIV-infected cells, rather than ones that enhance it. The worst case scenario is that immune boosting treatments could actually speed up the destruction of the immune system.

Dr Loveday argues that the true mechanism of immune destruction is likely to be a combination of the direct effects of the virus and the effects of the immune system. "I think the immune system contributes both to cell regeneration and to cell destruction. If the immune system has been so damaged that only the destructive parts remain then clearly you are on a hiding to nothing with any therapy. But while the immune response remains diverse then one has the hope of recruiting those regenerative immune responses to come to our assistance."

REFERENCE

Jay Levy's viewpoint article is published in The Lancet Vol. 345 pp. 1619-1621, 24th June 1995.

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