AIDS TREATMENT UPDATE, September 1995

Most medical efforts to halt or slow the progression of HIV infection have focused on anti-viral drugs. Virologists believe that if you can interfere with a virus' ability to reproduce, its damaging effects on human cells will be stopped or at least reduced. But HIV is not like most other viruses. It specifically infects the cells of the immune system - the very same cells designed to protect us from infections. The normal immune response to infections has the potential to stimulate HIV to reproduce and spread throughout the body.

Immunologists - as opposed to virologists - wonder whether we can use the information we are learning about the diverse functions of the immune system to help the immune system prevent HIV infection from progressing. In their search to do that many immunologists have focused on cytokines.

WHAT ARE CYTOKINES? Cytokines are proteins produced by many different cells of the immune system which act upon other cells. They attach to receptors on the outside of cells causing the target cell to produce a certain reaction, depending on the cell and the cytokine. Often the target cell produces other cytokines in response to the initial cytokine. This complicated relationship is called the cytokine network, and it is one of the most important ways that the immune system (which is distributed throughout the body) communicates and orchestrates appropriate responses to various challenges, including viruses, bacteria, fungi and even tumours. Most cytokines are produced by T-lymphocyte cells and to a lesser degree by monocytes and macrophages.

There is growing evidence that initial HIV infection disrupts the normal balance of cytokines by causing the levels of certain cytokines to rise. As the disease progresses to AIDS, the production of these cytokines declines whilst the production of another group of cytokines increases. Some scientists think that this change from one group of cytokines to the other group directly causes many of the symptoms associated with AIDS including wasting, lymphomas, neurological damage and dementia. Cytokine imbalances may also help HIV to target CD4 cells and the lymph nodes, leading to the progressive immunosuppression and the opportunistic infections that follow.

This theory - that the shift in cytokine balances causes the progression from HIV infection to AIDS - is called the Th-1/Th-2 theory. Th-1 refers to the group of cytokines that seem to be produced by T-lymphocyte or T helper cells (thus Th) in response to the initial HIV infection. This group of cytokines includes gamma interferon and interleukins 2 and 12 (IL-2 and IL-12). During the asymptomatic period of HIV infection, the levels of these cytokines remain high. This may itself help to suppress levels of Th-2 cytokines; for example gamma interferon appears to inhibits the production of Th-2 cytokines.

For those people in whom HIV progresses to AIDS, a shift begins to occur during this asymptomatic period. Levels of the Th-1 cytokines start to fall and levels of the Th-2 cytokines - interleukins 4, 5, 6 and 10 (IL-4, IL-5, IL-6 and IL-10) and Tumour Necrosis Factor (TNF) alpha - start to rise. Precisely why this shift occurs is not known. But one thing that seems to contribute to and amplify this shift is the way that high levels of one cytokine can affect the production of others. For example, high levels of IL-4 (a Th-2 cytokine) can stimulate production of more Th-2 cytokines (including IL-4 itself) creating a continuous loop, or vicious circle.

Th-1 cytokines are associated with a cellular immune response in which immune cells such as CD8 cells are used to fight infections. Th-2 cytokines are associated with a humoral immune response, which relies more on the use of antibodies.

AIDS-RELATED ILLNESSES Not all immunologists accept that the Th-1/Th-2 switch plays a deciding role in the progression of HIV to AIDS; an alternative possibility is that it is a response to, not a cause of, disease progression. However quite apart from the validity of the Th-1/Th-2 theory, there does seem to be evidence that high or low levels of certain cytokines are associated with certain HIV-related illnesses. In particular, some researchers believe that certain long-term infections that the body can't eradicate, such as MAI, may persist because they manage to switch on a Th-2 type of cytokine response.

People with HIV-related lymphoma often have high levels of IL-6, and a recent study suggests that the lymphoma may stabilise if treated with antibodies to IL-6 (abIL-6) to lower the IL-6 levels. Lowering IL-6 also seemed to reverse AIDS-related wasting, fevers and night sweats.

Another cytokine that has been linked to AIDS-related symptoms is TNF-alpha. High levels of TNF-alpha in the brain have been associated with the development of dementia and neuropathy. High TNF levels are also sometimes seen during microsporidosis and MAI infection.

CYTOKINE TREATMENTS The apparent link between abnormal levels of Th-2 cytokines and immune damage or AIDS-related illnesses has led some researchers to explore treatments that may correct these imbalances. For example, the Kobler Centre has started trials testing thalidomide, which reduces TNF levels, as a treatment for microsporidiosis and MAI (see AIDS Treatment Update issue 31). Thalidomide and other TNF inhibitors, such as oxpentifylline, are being studied as treatments for wasting.

At the same time, other scientists are seeking to boost levels of cytokines that are thought to be helpful in fighting HIV and other infections. A trial at St Bartholomew's Hospital in London is examining whether injections of gamma interferon can effectively replace the levels of this cytokine that are lost in people with HIV, and thus reduce the incidence of opportunistic infections.

But there are problems in embarking full steam ahead with cytokine treatments. Cytokine levels are inter-related, with changes in the levels of one cytokine affecting the levels of others. As reported in AIDS Treatment Update issue 28, early trials of IL-2 found that the drug of IL-2 can dramatically increase CD4 counts in HIV-positive people with high initial CD4 counts. But high doses can also trigger the production of TNF-alpha and IL-6 (among others). The study also found that IL-2 boosted blood levels of HIV because by stimulating resting T-cells into production the dormant HIV contained in some of these T-cells was able to replicate, spreading more virus.

Some researchers question the wisdom of any cytokine interventions, arguing that changes in cytokine levels may be an important and healthy part of the immune response to HIV and opportunistic infections. Additionally, no-one really knows where the 'domino effect' started by artifically altering cytokine levels may end. It is quite possible that the ultimate effects may lead to unforeseen problems.

TESTS Another possibility is to use tests of cytokine levels to help in treatment decision-making, just as CD4 count and (increasingly) viral load measurements are sometimes used. For example, if the switch from Th-1 to Th-2 is proved to correlate well with an increased risk of progressing to AIDS, it might make sense to start taking anti-viral treatment once the switch is detected. This might have an advantage over using a fall in CD4 count as a guide to starting treatment, because the Th-1/Th-2 switch usually starts before the accelerated in CD4 count associated with progression to AIDS.

However, this is not yet practical in the clinic. The most common way of measuring cytokine levels is to stimulate immune system cells from blood samples and then clone what these cells produce until the cytokines reach a high enough levels that they can be measured using current techniques. But by stimulating immune cells in this way the results obtained may not be an accurate reflection of what is happening in the body, and the process is currently quite expensive.

An alternative measure of cytokine levels is found by taking larger amounts of blood cells and allowing them to grow in the laboratory over time (called 'culturing') to see what is produced. This technique is even more expensive because it is very labour-intensive, taking hours of work for just one sample, and many samples need to be taken over time for an accurate assessment of what is happening to cytokine levels in the individual.

So while cytokines may well play an important part in the progression from HIV to AIDS and in many AIDS-related illnesses, much more research and scientific progress need to take place before they become a routine part of HIV management.