Immune cells communicate through chemical messages. For example, one chemical might direct cells to where they are needed to fight off an infection. Another may make cells reproduce, cloning themselves to build an army to combat a specific infection. These chemicals are called cytokines.
Scientists have been trying to decipher the chemical language of the immune system to learn how to harness it for use in the fight against AIDS. This article provides a general picture of cytokine therapy to date -- approved therapies, those currently in large studies, those entering studies in HIV soon and a glimpse at tried and failed approaches.
One of the great clichés of popular writings about medicine is the claim that some products "boost the immune system." This is far easier said than done, nor is it always clear that the goal, even in HIV disease, should be to "boost" any aspect of the system. Just as often, the real goal may be to suppress or modulate some aspect of the immune response.
Therapies designed to influence the immune system are called immune-based therapies. The field of immune-based therapies (IBTs) is still in its infancy, but not so new that the reality of IBTs is outside the grasp of day-to-day use in the practice of medicine. There are currently approved and proven cytokine therapies that are routinely used by people living with HIV. These include cytokines like interferon-alpha, granulocyte colony stimulating factor and erythropoietin-alpha.
Interferon-alpha is most known in the setting of HIV as a broad spectrum antiviral. While test tube studies show some anti-HIV activity of interferon-alpha, studies in people have been conflicting. Other facets of its impact on immune functions are also being explored. For example, studies are underway to see if its use can prevent diabetes. It has also been proven to be useful in treating non-viral cancers, such as malignant melanoma. It is available in standard and "PEG" (pegylated) forms. These forms combine it with PolyEthylene Glycol, which stabilizes the interferon and keeps it in the bloodstream longer, thus improving its effectiveness.
IL-2 is also being evaluated for its potential to heighten responses to therapeutic HIV vaccines. A few small studies are including IL-2 as part of acute infection and early disease treatment and structured treatment interruption (STI).
Two cytokines are drawing increased interest from researchers for their potential in treating HIV infection. These are interleukin-7 (IL-7) and interleukin-15 (IL-15).
The first human study of IL-7 is recruiting volunteers in the setting of cancer. HIV researchers are watching this study and will learn about dose, schedule and side effects that will be further evaluated in HIV studies. While there is increasing interest in using IL-7 for HIV, there are concerns about safety. IL-7 activates HIV and particularly a very aggressive form of HIV, called syncitia inducing (SI) or R4-dependent virus. It's possible that this concern could be lessened by giving IL-7 with anti-HIV medications. Some research in animals suggest that short-term activation of HIV by IL-7 might be a good thing as it may decrease the reservoir of HIV lurking in resting cells. The major barrier to moving this research forward is that no company committed to HIV research currently makes a form of quality controlled IL-7 suitable for large human studies.
Several cytokines have been looked at in the context of HIV. Interferon-gamma enhances the function of cells that control mycobacterial infections, including tuberculosis and MAC. It has been studied together with anti-TB treatment in people with TB and HIV. It is also being looked at as an adjunctive therapy to enhance vaccine effects. Early studies suggest that low doses of interferon-gamma may control HIV whereas high doses may promote HIV replication. Interferon-gamma, however, is also associated with cell activation, which isn't necessarily a good thing. Over the years, increased interferon gamma levels have alternately been described as both a good thing and a bad thing.
This point is important when considering the challenges of researching cytokines. In the body, cells are producing these chemicals at very, very small -- nanomolar -- concentrations and together with other cytokines. The combination of cytokines, in varying concentrations, elicits different immune responses. At low doses IL-2 preferentially stimulates natural killer cells, while at higher doses, delivered intermittently, it stimulates CD4+ cells to reproduce. When IL-2 is given at high dose daily it produces no appreciable effect on CD4+ cell count. When it is given for five days every eight weeks, the effect is profound and pronounced. The challenge with cytokine research is not merely to understand the various biologic functions of the cytokine, but also how best to give the therapy to achieve the desired responses.
These are a handful of cytokines that have been studied in the setting of HIV. While they failed to show benefit, it may be that at different doses, given intermittently as opposed to daily, or combined with other cytokines, they will one day be researched again and show promise.
As research advances and tools are improved to understand the immune system, more is being learned about cytokines. There is increased interest in harnessing the language of the immune system to direct its responses and improve health. This research holds great potential, though the road to realizing it will likely be riddled with failed experiments and confounding results. Cytokine therapy is not merely a tool of the future -- years from the grasp of our medicine cabinets. To the contrary, several cytokine therapies are now routinely used by many people living with HIV.
Furthest along in the research pipeline is IL-2. Answers about the value of IL-2 in combination with anti-HIV therapy are expected within the next 2-3 years. The hottest new tickets in the cytokine town are IL-7 and IL-15. Although neither has made a debut in studies of people with HIV, there's not an immunology conference in HIV where they're not the buzz. Activist involvement is needed to ensure these two therapies are researched in HIV.
A handful of other cytokines have been tested in HIV, with either negative or confounding results. They may make comebacks as more is learned about the language of the immune system and how it acts.
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