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Immune-Based Therapies

By Debra Johnson, NP,PA-C

Fall 1999

Human Immunodeficiency virus (HIV) is the retrovirus that is transmitted through semen or blood. The World Health Organization (WHO) estimates that over 13 million young adults have been infected with HIV and over 2 million have already developed AIDS, most of whom have died. Approximately 5,000 new infections occur every day throughout the world and here in Los Angeles County, between 1,400 and 2,000 new cases are diagnosed every year. By the turn of the century WHO predicts that more than 30-40 million will have been infected and that more than half of these infections will be in women.

The development of highly active antiretroviral therapy (HAART) has resulted in improvement in survival and should be considered the mainstay of current therapy for HIV infection. However, despite the fact that many persons with HIV (PWHIV) have had tremendous success with complete suppression of vRNA, many have experienced limitations. The duration of complete viral suppression can be shortened by a long history of previous drug therapy, intolerance, pill burden or the sequential (one drug at a time) addition of drugs.


What Are Immune-Based Therapies

Opportunistic infections and malignancies (i.e. lymphoma or cancer) are generally the result of an immune system that is suppressed, not by the HIV infection. Immune-based therapies target the immune system directly to improve function or prevent further destruction of immunologic deterioration. HIV disables the immune system by destroying CD4+ cells, leading to increased risk of potentially life-threatening opportunistic infections, such as Mycobacterium avium complex (MAC), Pneumocystis carinii pneumonia (PCP), and cytomegalovirus (CMV). Boosting the T-cell counts will help combat these diseases.

Cutting-edge immune therapies involve one of several naturally occurring chemicals produced by immune cells, called cytokines. Several cyto-kines have been studied. Some of these cytokines include interleuken-2 (IL-2), interleuken-12 (IL-12), interferon, bone marrow transplants, passive immunization with hyperim-mune globulin (IVIG) and immunization with whole inactivated HIV or proteins such as gp160 (vaccines).


Interleuken-2 (IL-2)

IL-2 has been studied since 1983, and in the test tube it can turn one cell into thousands. IL-2 is a cytokine that is produced primarily by the T-helper cells. IL-2 leads to T-cell replication and differentiation into other CD4 cells such as CD4 helper cells, CD8 cytotoxic cells, antibody producing B cells, natural killer cells (NK), and monocytes/macrophages. In vitro (in the test tube) studies showed that IL-2 could restore NK activity and cytomegalovirus (CMV) specific immunity. This was enough information to feel that PWHIVs, especially patients who have advanced disease, may benefit from the use of IL-2. This was the initial rationale to design a clinical trial to study IL-2 in humans.

Side effects are dose-limiting (related to the amount of IL-2 you receive). These side effects include fevers, chills, rigors (uncontrollable shaking), sweats, muscle and joint pains, nausea, vomiting and fluid retention. There may be increases in liver function tests, abnormalities in sodium, potassium or other electrolytes. In severe cases hyperthyroid, cardiomyopathy and congestive heart failure have been reported.

Because IL-2 stimulates activity of lymphocytes and this can increase HIV replication, IL-2 must be used only after viral replication is completely suppressed with HAART. This minimizes the risk of potential increases in viral load. Very high increases in CD4 cell counts have been reported, but the clinical benefit is not clear yet. Research needs to address whether PWHIVs with very low T-cell counts can benefit from IL-2 therapy. At this time IL-2 is not recommended to be used outside of the research arena (clinical trials).


Interleukin-10 (IL-10)

IL-10 has been shown to play a role in viral immunity and may become an immunomodulator that may suppress HIV activity. Studies are underway to determine if IL-10 could also increase the replication rate of HIV by increasing the number of immune cells. IL-10 is still only available in research.


Interleukin-12 (IL-12)

IL-12 has been used in the treatment of mycobacterium infections, cancer and is now being looked at in HIV infection. IL-12 is a cytokine that has been shown to improve the T-cells ability to fight off infections. IL-12 enhances the ability of the immune system and kills tumor cells. Bacterial infections, especially MAC, can be difficult to treat in PWHIV because of both T-cell depletion (low numbers of T-cells) and the decrease in function of T-cells.

In several studies PWHIV infected with MAC were given both antibiotic and IL-12 and it was found that these two treatments were very synergistic (worked better together, than either separately). IL-12 has a relatively low degree of toxicity and appears to produce few side effects. IL-12 is currently in clinical trials and additional data should be available in the beginning of the year 2000.


Interferon

Alpha interferon is currently approved for the treatment of AIDS-related Kaposi's Sarcoma, but it has also shown some antiviral effect in test tubes. Clinical trials have shown conflicting results from some differences to no differences. Side effects can resemble flu like symptoms and it appears to have a limited role in fighting HIV infection, but is currently being used to help control the progression of thrombocytopenia (low platelets), hepatitis, especially hepatitis C and KS.


Conclusion

Immune-based therapy is a relatively new field of study. Many immune-based therapies have been evaluated, but at the present time immunotherapy has been shown, in controlled clinical trials, to provide a clinical benefit to every patient. The two most promising immunotherapies are interleukin-2 (IL-2) and interleukin-12 (IL-12). These drugs have been studied with mixed results in PWHIVs.

Levels of IL-12 and IL-2 appear to have a direct correlation to cellular immunity. Treatment with these two substances may strengthen immune function and decrease the pace of disease development. Recombinant (genetically made) forms have been developed as hopeful treatments for cancer, HIV, and other infectious diseases. But at the present time these compounds are still in clinical trials and not available for use outside of clinical trials.


Gene Therapy

Neutralizing antibodies are unable to access the virus because there is a sugar coating that protects the virus. The virus attaches to the CD4 receptor site through the Gp120 and the sugar coating disappears. Gp41 is the part of the virus responsible for viral entry into the T-cell (CD4) by fusing to the wall of the T-cell. HIV is different than any other retrovirus because it has a dense core that appears cone-shaped.

Once the virus enters the CD4 cell, viral proteins incorporate into our DNA. HIV-1 has genes that are responsible for viral production and they are called tat, rev and nef. These genes are the regulatory proteins. What this means is that they are the proteins that are responsible for deciding to replicate HIV virus or lay asleep. Replication does not take place in resting cells such as macrophages, but can only multiply when the cell is actively replicating itself.

Vif, Vpu and Vpr are the late proteins responsible for transport of the virus into the nucleus. These genes are also responsible for packaging the proteins and budding (leaving the T-cell) of the new virions. This process allows the virus to leave the cell and find other T-cells that are not infected.

There are 3 types of gene therapy; gene therapy that induces resistance to HIV infection (vaccine), give therapy that interferes with HIV viral replication (gene therapy) and give therapy that would induce antiviral immunity (gene immunotherapy). The biggest problem with gene therapy is to find a suitable vector (mode of transportation). The most commonly used vector at present is a murine (mouse) retrovirus.

Use of HIV as a vector is a promising option that is currently in research. One approach that is having some success has been the use of a gene gun. This technique works by taking out the host cells and bombarding the cells with nucleic acids and then returning them back to the host. The down fall of this therapy is that each time this procedure needs to be done, it has to be done outside the body.


Another Approach

Another gene therapy method known as the decoy RNA method uses decoy RNA to bind to the sites Tat and Rev. The hope is that these decoys will soak up available Tat or Rev protein and the virus can not replicate. Another approach known as antisense RNA that binds to known HIV RNA and prevents HIV from being made into proteins. Problems with technique include difficulty in getting antisense RNA to the right target.

Lastly, another approach to gene therapy would be to introduce a toxin so when HIV is triggered to replicate, the toxin would be released destroying the virion that may be introduced into the cell. One problem that still needs to be overcome is the fact that the body is very efficient in making antibodies against proteins. A way to get the protein to it's target without the body knowing proved to be a problem.


Information

More information needs to be collected for gene therapy before we know whether there is any benefit by using these types of therapies. Currently there are ongoing clinical trials that should give us answers for the future. For now the best therapy available is early detection and striving to keep the immune system intact and the body as healthy as possible.


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