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Coaxing the Immune System to Fight Back

By David Pieribone

August/September 2001

Coaxing the Immune System to Fight Back

Current treatments for HIV disease are not cures. The medications people now take to stay healthy only suppress HIV enough so that it does not cause harm. As more and more people take HIV medications it is becoming clear that popping pills for the rest of one's life is probably not a option.

For many, the initial toxicities associated with these medications make longtime use impossible. For others able to deal with the short-term side effects, lipodystrophy, heart disease, osteoporosis, liver damage and neuropathy are frightening thoughts. Even with better medications being developed, the perfect drug combination may never exist.

While a cure for HIV may not be feasible for some time to come, researchers are looking to the body's immune system for help.

For 20 years science has been studying HIV and the immune system, trying to figure out why unlike so many other diseases, the body just can't seem to control HIV. What they have found may one day enable us to teach the immune system to control HIV and keep us healthy.

Understanding how the immune system reacts to viral infections has been no easy task. When a doctor in Los Angeles described the first case of AIDS 20 years ago, the immune system still had many mysteries. Today, researchers understand a lot more about how the immune system successfully fights off or suppresses viral infections.


How the Immune System Works

To protect the body against disease, the immune system must be able to fight off viruses, bacteria and other infections.

The immune system is able to manage an astounding number of infections by either destroying them completely or keeping them in check so that they cannot harm the body. Everyday the body is involved in repelling or destroying invaders that would otherwise kill us.

In order to keep viruses, bacteria and the like in check, the immune system employs a number of strategies. If an invader manages to get past the body's first line of defense, the skin, the immune system is ready with small molecules called antibodies. Cells of the immune system called B-cells produce antibodies. Antibodies are able to attach to invaders and stop them in their tracks so that they cannot infect other cells, slowing down the infection.

After antibodies attach to an invader, they attract attention so the immune system can see the invader and send large cells, called macrophages, to devour the invader. If the invader slips by the antibodies, the immune system has a few back-up plans. Cells called killer cells are able to recognize infected cells and destroy them, keeping the infection from multiplying out of control and damaging the body. Immune cells that produce and secrete a variety of substances called cytokines offer another layer of defense. Cytokines or chemical messengers can interfere with the ability of viruses to attach to cells and are able to stimulate the production of more immune cells.

Most everybody is familiar with the chicken pox. This disease is an infection caused by a virus called Varacella Zoster which usually infects children and causes small pox or sores to form on the skin. Most everyone has had the chicken pox and lived to tell about it because the immune system produces antibodies and cells that control it.

Many people are unaware that the chicken pox virus is never actually destroyed and hides in the body as long as we live. The chicken pox virus is one of the many viruses that the body does not destroy completely, but keeps in check so that it can't cause harm. Because this virus hides in nerve cells, the immune system cannot find it. When it comes out of hiding for an attack, the body is waiting to knock it back down.

However, when the immune system grows weak with old age or is compromised when someone gets chemotherapy for cancer or has AIDS, the chicken pox virus can come out of hiding and make a nasty return. Its reincarnation is called the shingles, a rash that can be very painful and sometimes quite dangerous.

The herpes virus is also able to hide from the immune system. This annoying virus causes sores on the lips and genitals and is easily transmitted. Just like the chicken pox virus, herpes is never eradicated and makes return attacks on the body when defenses are low.

Antibodies, killer cells and inhibitory cytokines control viruses like herpes and chicken pox that never get destroyed completely.

Similar to other viruses, HIV is able to hide from the immune system by constantly changing its disguise. What is different about HIV is that it is an infection of the immune system.

When a person initially becomes infected with HIV the immune system does a pretty good job of suppressing the infection and re-supplying cells lost in the battle. Slowly, over time HIV wins out by waging a constant and chronic assault on the cells of the immune system. Eventually, HIV destroys the very part of the body that keeps viruses and other infections in check.

For more than 99 percent of people infected with HIV, the virus, if left untreated, will cause the immune system to malfunction leading to acquired immunodeficiency (AIDS). A severely weakened immune system allows other infections (called opportunistic infections) to take over the body, eventually causing death.


Immune Control of HIV

So what about the small number of people who get HIV and manage to stay healthy?

A number of years into the HIV epidemic, doctors began to find a few people who were infected with HIV but managed to stay healthy for long periods of time without medication. Although this number is very small (less than 1 percent) it was proof for some that the immune system could control HIV. The hope was that researchers could find a way to reconstitute the immune system in sick people so that it could fight HIV.

Reconstituting the immune system has been attempted since HIV was first realized to cause immunodeficiency. But the prospects for restoring the immune system became more realistic with the advent of highly active antiretroviral therapy (HAART). HAART suppresses HIV to very low levels giving the immune system a chance to partially restore itself. The problem is that even with the virus suppressed, the immune system doesn't seem to develop a strong enough response to HIV to keep it in check once the medication is stopped.

Researchers began to look at ways to teach the immune system to recognize HIV. To do this they first had to understand how some people with HIV were able to manage the virus without the help of medication.

Although researchers do not understand how long-term non-progressors keep HIV in check, they have uncovered some important clues. For starters, people whose immune systems are able to manage HIV seem to have a very active killer cell response. And unlike most people infected with HIV, long term non-progressors produce a variety of antibodies that target many parts of the HIV virus.

Researchers also point to the production of a variety of cytokines (chemical messengers of the immune system). New research indicates that long-term non-progressors have increased levels of these cytokines that inhibit HIV from entering cells and stimulate other immune cells to identify HIV. As research continues on how the immune system and HIV interact, a number of approaches seeking to restore the immune system are being studied in animals and in clinical research.


Treatment During Acute Infection

Acute HIV infection refers to the period of time (usually the first 180 days) after a person has been first infected with HIV.

Researchers have shown that by limiting viral replication during acute infection (through the use of HAART) T-cells are able to mount and maintain a specific response to HIV. Unfortunately, the killer cell response that is needed to contain infected cells is not so good.

Researchers have experimented with interrupting treatment after an initial course of HAART and have had varying results. Some participants were able to control HIV after a few treatment interruptions while others were not successful and had to restart medications. Studies in people who have had HIV infection for many years (chronic infection) have not been so successful.


Therapeutic Vaccines

When we think of a vaccine we usually think of something that prevents an illness before it happens by getting the immune system to recognize to a disease it has never seen.

Therapeutic vaccines aim to teach the immune system how to fight HIV after the fact. Early studies of therapeutic vaccines yielded disappointing results. However many of these early trials were done before the advent of HAART.

Researchers theorize that a combination of HAART to suppress the virus and protect the immune system and a therapeutic vaccine may do the trick. Currently there is controversy about what kind of response an HIV vaccine must elicit. Some researchers suggest that a strong antibody response is not sufficient to control HIV and that the killer cell response must also be stimulated. The challenge to researchers is to develop a vaccine that not only produces a variety of antibodies to recognize the constantly changing virus but one that also teaches killer cells to seek out and destroy cells that are hiding HIV inside.


Cytokine-Based Therapy

Cytokines, also known as chemokines, are molecules produced by immune cells that modulate the immune response. Some cytokines stimulate the production of new cells while other cytokines may directly attack viruses, bacteria and other invaders.

Early in the epidemic researchers experimented with a substance known as interleukin-2 (IL-2). IL-2 is a cytokine (chemical messenger) secreted by activated T-cells. IL-2 is able to stimulate the production of new T-cells. Early experiments with IL-2 did not prove favorable because even though IL-2 increased the number of T-cells, the virus was able to infect the new cells. With the advent of HAART and the ability to suppress HIV replication, researchers are again looking at the potential of IL-2 to boost the immune system. New research on IL-2 at the National Institutes of Health suggests that besides increasing the number of T-cells, IL-2 may make the cells live longer. Il-2 is now being studied in conjunction with therapeutic vaccines and treatment interruptions.

Other cytokines such as IL-12, MIP-1 alpha, MIP-1 beta and RANTES are also being studied. In the test tube IL-12 has been shown to increase the function of killer cells, which may increase the immune system's ability to destroy HIV infected cells. MIP-1 alpha, MIP-1 beta and RANTES are chemokines that inhibit the ability of HIV to attach to cells. Other cytokines may interfere with HIV once it is inside the cell.


Coaxing the Immune System to Fight Back

Treatment Interruptions

Interruptions in HIV treatment may provide an alternative or adjunct to therapeutic vaccination. Before discussing this approach, it is important to stress that treatment interruptions are only experimental and should not be attempted at this time outside the context of a clinical trial.

Treatment interruptions aim to use the patient's own virus to stimulate the immune system. Although varying approaches are being studied, the basic idea is the same. HAART is used to suppress HIV and allow the immune system to rebuild important cells. Once this has occurred, treatment is stopped and HIV is allowed to reproduce so that the immune system can be exposed to the virus. Before the levels of virus get too high, treatment is started again. This is done a number of times to give the immune system a chance to identify HIV and develop an immune response while at the same time preventing HIV from getting out of control. While there are no data available yet to show that this approach will work, there are a number of individual reports that suggest there may be some role for treatment interruptions.


Gene Therapy

Gene therapy refers to the genetic manipulation of cells to convert them to anti-HIV killer cells.

Clinical studies are currently under way to test whether these genetically altered lymphocytes are able to recognize HIV-infected cells and destroy them. The hope is that this approach will allow the immune system to identify cells and reduce the number of cells that harbor HIV.


Passive Antibody Therapy

Antibodies are effective in helping control many diseases. Many years ago experiments were conducted with serum (the liquid part of blood that contains antibodies) donated from people who were doing well for a long time despite HIV infection. The serum was transfused into people who were sick. Despite some promising results, research was not continued.

Recently, this approach has gained renewed attention. Animal studies conducted by Ruth M. Ruprecht, M.D., Ph.D., an immunologist at the Dana Farber Cancer Institute, have successfully prevented infection with a virus similar to HIV after the infusion of certain antibodies directed against the virus.

If this approach continues to be successful, applying the concept to people already infected with HIV may be possible.


Conclusion

Immune-based therapy is the next frontier in AIDS treatment. Recent studies have shown that manipulation of the immune system to control HIV is possible. Although these approaches are not ready for prime time, data from ongoing studies in the next few years should yield some answers.

David Pieribone   David Pieribone is Associate Director of AIDS Project Los Angeles' Education Division. He can be reached by calling (213) 201-1520 or by e-mail at dpieribone@apla.org.


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This article has been reprinted at The Body with the permission of AIDS Project Los Angeles (APLA).




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