Project Inform - September, 1998

The ability to potently suppress HIV replication for an extended period of time opens opportunity to study how well the immune system is able to correct defects caused by viral replication. It creates opportunity to try and rekindle the immune response using methods often considered too risky while viral replication continued at a high rate. The following topics from the meeting highlight only a few of the recommendations for future research.

The Environment

A recurrent topic of discussion was the state of the immune environment. A key question was whether the environment where cells are derived (e.g. bone marrow) and where they mature (e.g. thymus) are intact. Much work, largely inspired by previous IRTT meetings, has proceeded with regard to understanding the role and state of the thymus in HIV disease. Simultaneously, two studies have been conducted on thymus transplantation, one funded by Project Inform in association with the Foundation for AIDS and Immune Research.

Dr. McCune of the Gladstone Institute in San Francisco conducted CT scans of the thymus in people at varying stages of HIV disease and across the spectrum of age. Common belief in HIV disease has long been that the thymus is prematurely destroyed or damaged. However, when comparing CT scans of HIV-positive and -negative individuals regardless of age, Dr. McCune found that people living with HIV tend to have more detectable thymus material. Moreover, people with HIV in mid-stage disease (e.g. CD4+ cell counts of 300-500) appear more likely to have detectable thymus material compared to those in early-stage (e.g. CD4+ cell counts >500) or more advanced-stage (e.g. CD4+ cell counts <300) disease. These results have been quite encouraging. It remains to be seen whether thymus material will eventually regenerate in people with low CD4+ cell counts if the virus is adequately suppressed. If the thymus does not regenerate, thymus transplantation or other approaches to augment its function may need to be further explored.

In light of these findings, some participants suggested it may now be appropriate to reopen the study of several compounds, including thymic factors which are believed to promote maturation of thymus cells. While thymic factors have been studied for over 35 years for a variety of medical conditions, research has been overwhelmingly disappointing. Older studies typically pitted thymic factors against specific disease conditions and asked whether they led to clinical improvement. Newly proposed studies would instead ask if the use of these compounds results in the promotion of new cells maturing through the thymus. Prior, unsuccessful research on thymic factors in HIV disease was conducted before the advent of HAART. Think Tank participants recommended that these types of approaches be re-examined in light of recent advances in HIV therapeutics. In addition to re-evaluating thymic factors, including Thymic Humoral Factor, Thymosin-alpha 1 and thymopentin, the group noted a number of other compounds which might have an effect on cell maturation. These compounds include flt3 ligand, IL-2, recombinant human growth hormone (rHGH, Serostim^®) and Insulin-like Growth Factor (IGF-1). Similarly, it was recommended that additional studies be conducted on therapies used in the treatment of HIV disease which are known to inhibit cell maturation in the thymus, including interferon-alpha, androgens, testosterone and glucocorticoids.

Surprisingly, discussion revealed that very little is known about the status of bone marrow in patients throughout the course of HIV disease. If the bone marrow environment is "hostile" or cannot support new cell development, bone marrow transplantation or approaches which augment the maturation of bone marrow cells into the spectrum of immune cells may need to be applied. To move this important research forward, a working group was formed to develop the needed research protocols. Understanding the status of the bone marrow may be critical in understanding how the immune system ultimately fails in its fight against HIV.

Emphasis on New Technologies

A persistent obstacle in immune restoration research is the lack of tools to measure immune responses and assess the status of the immune system. Developing new tools remains a high priority recommendation from Think Tank participants. An example is the need for cell labeling techniques which can safely be used in humans. It is difficult to understand whether or not cells are migrating out of the bone marrow and maturing properly, or even track where cells go in the body, without ways to mark cells and follow what they do. Dr. McCune and Dr. Hellerstein of UC Berkeley have developed a labeling technique which appears very safe and is being moved forward into studies in people with HIV. The technique involves intravenous infusion of something akin to sugar water. Cells will absorb the material and researchers will be able to track what happens to these cells over time, where they go and hopefully learn what they do.

Participants unanimously called for intensification of efforts to define, develop and validate tools to measure immune responses. A working group formed and discussed the best ways to move this important research forward. Over the upcoming year the group will interact with the National Institutes of Health to get new information gathered and analyzed. Also, a more comprehensive and descriptive list of immunologic assays will be developed to prioritize further development of promising new tools.

Advanced-stage Disease Therapies

A number of immune-based therapies exist that need to be further explored in the context of HAART in people with advanced-stage HIV disease. These include interleukin-2 (IL-2) approaches which might enhance thymus function, immune suppressive approaches, such as cyclosporine and a re-evaluation of approaches which may be useful in boosting immune responses, such as therapeutic vaccination. Some studies are already underway, having been initiated by Think Tank participants prior to the meeting. A study of low dose IL-2 use in people with advanced-stage HIV disease (e.g. CD4+ cell counts <200) is currently being developed. A study of cyclosporine in people with CD4+ cell counts >300 is enrolling in San Francisco, and a study of the drug in people with more advanced disease is enrolling at Case Western Reserve Hospital in Ohio. Researchers are currently evaluating which thymus enhancing approach to test in a study and others are considering which therapeutic vaccine approaches to re-evaluate.

Through the Think Tank process, Project Inform brings together top researchers from around the world, working inside and outside the field of AIDS, to come together in unique ways to plan new directions for immune restoration research. In the few short years since the first Immune Restoration Think Tank, the project has received international acclaim for moving this field of research forward leaps and bounds. In addition to being featured at many national and international AIDS conferences as a model for community interaction with HIV research, the project has yielded great success in pushing the frontiers of science and fostering research efforts into novel approaches targeting advanced HIV disease. 

For more information on Project Immune Restoration and the Immune Restoration Think Tank, call the Project Inform National HIV/AIDS Treatment Hotline and request the Immune Restoration Think Tank Discussion Paper.

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The original of this article can be found at http://www.projinf.org/pub/25/thinktank.html