Interleukin-2 (IL-2): A Path Toward Functional Eradication?
Recent research has demonstrated that antiviral drugs can be extremely effective in reducing or practically eliminating all evidence of HIV in the bloodstream and in actively replicating cells. However, careful study shows that HIV infection persists despite this.
In one study, which included people treated with Highly Active Anti-HIV Therapy (called HAART) very early after initial infection with HIV, virus capable of reproducing was found in every individual treated despite the fact their HIV levels were below the limit of detection with currently available tests. The apparent cause of this is the presence of a population of resting T-cells which are infected by HIV. While in their resting state, the cells provide a near perfect harbor for HIV. The immune system doesn't recognize them as infected cells because they aren't expressing virus or the surface markers that would indicate they are infected. The immune system can only detect the presence of HIV when a cell is actively producing new virus, which identifies the cell as infected. Similarly, anti-HIV drugs can play no role with resting cells for the same reason. Drugs can only interfere with the production of new virus or the infection of new cells by active virus. Therefore, they can't do anything when the virus is resting inactive inside a cell. These resting, or quiet cells, are believed to be the major reservoir of HIV infection.
These cells can persist indefinitely, and virus lurking within them can rekindle active HIV infection. When and if these cells become active, they can begin producing virus. This reservoir of resting cells is believed to be one of the major barriers to completely eliminating HIV from a person's body.
Researchers who are attempting to achieve eradication (e.g. the complete elimination) of HIV are now planning to test different methods of converting these resting T-cells into active cells. Once activated, these cells should be vulnerable to the immune system and to antiviral drugs, just like other cells. Interleukin-2 (IL-2 or Proleukin®) stimulates resting cells, thus exposing both virus and cells to the effects of anti-HIV drugs as well as the immune response against HIV. Using IL-2 therapy may help to decrease or eliminate this hidden pool of virus.
In August, Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID, the institute which funds the majority of AIDS research efforts worldwide), presented new findings from an exploratory study of IL-2 used in combination with potent anti-HIV therapies.
At the International AIDS Conference in Geneva, Dr. Fauci and his colleagues raised the question of whether people treated with HAART plus IL-2 are any different from those treated with HAART alone. Specifically, they wondered whether IL-2-treated patients would have similar or different levels of the resting, infected T-cells compared to people on HAART alone.
After Geneva, they conducted a study to answer this question. The study compared two groups. The first consisted of 13 people with viral load levels below the limit of detection for 6 months or more using a very sensitive test (limit of detection 50 HIV RNA copies per ml). All were participating in NIH studies of HAART and IL-2. The second group recruited volunteers taking a HAART regimen for 6 months or longer and who had viral levels below the test's limit of detection. The two groups were very similar with regard to baseline CD4+ cell counts and viral load, length of prior therapy with HAART and other characteristics.
The research team then used sensitive tests to look for the presence of HIV DNA inside resting T-cells capable of reproducing (replication competent virus). Initially, they looked at about 10 million cells per individual. This has been sufficient in other studies to find infected cells and replication competent virus in virtually all HIV-infected people. Replication competent virus was readily found in resting cells in all 13 people who received HAART alone. In six people who had received HAART in combination with IL-2, however, the researchers could not detect replication competent HIV or latently infected cells.
Five of the six individuals who had been receiving the IL-2-containing regimen and had no detectable replication competent virus were studied further. Even more sensitive tests were run by searching through greater numbers of cells, more than 300 million cells from each person. Despite this intensive unprecedented search for the virus, researchers were still unable to find replication competent virus in three of the five individuals. To make sure this wasn't a temporary phenomenon and recheck their accuracy, the tests were repeated several weeks later in all six patients. The results were nearly identical, except this time the researchers searched even further, through more than 400 million cells, without finding HIV in the same three people.
Although virus was not found when looking at more than 300 million cells, it does not necessarily mean that virus has been completely eliminated from these people. To make such a claim, Fauci said one would technically have to examine every cell in the body, and no one is likely to ever do that. An even more intensive search is underway now looking for virus in deeper immune compartments, such as the lymph tissue. The next step, underway now, is to sample lymph tissue from the rectal mucosa and to examine spinal fluid.
The relevance of these observations might only be understood when or if these few people choose to stop their anti-HIV therapy. If there are still extremely small amounts of virus somewhere in the body, stopping HAART might allow the virus to re-establish itself and rekindle the fires of HIV disease. The real question is not whether HIV is completely eradicated, but whether there is enough of it still present to rekindle an active state of infection.
There is already some indication that full eradication is not necessary to prevent recurrence of active infection. For example, more than 10 patients in the US and Europe are currently being studied who have already gone off therapy on their own choosing. Whenever researchers have looked, these patients have measurable levels of replication competent virus -- unlike those in Fauci's new study. Yet these 10 people have been off of all anti-HIV therapy from 3 to 18 months without experiencing a return of measurable viral load. Fauci's patients would seem to have at least as good a chance as these people of successfully stopping therapy.
Preliminary results from this study are extremely encouraging and go beyond any data reported elsewhere. Still, another larger study needs to be designed quickly to confirm the findings. While in laboratory studies IL-2 appears to stimulate HIV replication, it may be that when used with anti-HIV therapy, IL-2 may help flush the reservoir. That in turn may expose virus to the effects of anti-HIV therapy as well as the immune response against the virus and then ultimately assist in more greatly decreasing the amount of HIV in the body.
IL-2 studies in people with HIV show that the therapy has the most profound and dramatic impact on CD4+ cell count than any therapy in the history of AIDS research. Numerous studies have confirmed the ability of IL-2 to effect pronounced CD4+ cell increases over and above what is realized with anti-HIV therapy alone. Thus far, lab studies suggest that CD4+ cells increased as a result of IL-2 therapy appear just as normal and useful as cells generated after successful HAART therapy.
It remains unclear if these increases will contribute to decreases in the risk of developing HIV-related infections or prolonged survival, though there seems to be no reason to expect otherwise. A study to answer this question is being planned and will hopefully begin to enroll early next year. A component of the trial, being conducted through a community based clinical trial network (CPCRA), is currently opening in sites throughout the US. For more information about trial sites, call 1-800-TRIALS-A and ask for CPCRA IL-2 study sites in your area.
Personal Decisions About IL-2 Therapy
While the growing bulk of results from IL-2 studies are increasingly encouraging, those contemplating becoming involved in an IL-2 study should be aware the therapy can be hard on patients. The most common side effect associated with IL-2 is mild to severe flu-like symptoms. Nearly everyone using IL-2 can expect to experience this side effect during the time therapy is taken (e.g. the 5-day course of IL-2).
IL-2 therapy is not taken every day. It is cycled and taken for 5 days in a row, every 8 weeks. Therapy is delivered through injection directly under the skin (subcutaneous). Time between cycles may be extended in IL-2 recipients who realize pronounced and prolonged CD4+ cell increases.
In a recent report on the long-term follow up of people in a NIAID study of IL-2, the average duration between cycles to maintain CD4+ cell counts at about 1,200 was 1 year. However, the individuals in this study had very high CD4+ cell counts (about 600) to start. This kind of immediate response is not expected among people who initiate IL-2 with lower CD4+ cell counts, where increases may take longer to realize. Sustaining those increases may require continued and frequent dosing.
For more information on IL-2, call Project Inform's National HIV/AIDS Treatment Hotline and request the IL-2 Fact Sheet.
This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.