Important note: Information in this article was accurate in April 2000. The state of the art may have changed since the publication date.
Summary of the Eighth Immune Restoration Think Tank
Project Inform Perspectives 29 - April, 2000
Project Inform hosted the eighth meeting of the Immune Restoration Think Tank: The Dobson Project (IRTT), October 8-10, 1999 in Chicago. Researchers from around the world, in partnership with community activists, convened to review data from ongoing projects, previously inspired through the Think Tank effort, and discuss new strategies and areas of focus for immune reconstitution research in people with advanced stage AIDS.
Participants spent the weekend discussing and planning actions around a variety of topics, ranging from cell therapy to bolster immune responses against HIV to strategic therapy interruptions as a way to achieve several possible goals of therapy. The following are four highlights from the discussions:
There is a need for the Food and Drug Administration to convene a meeting to determine what types of studies should be required to prove the usefulness of immune-based therapies for HIV infection. The most important question is whether there is any alternative to large, clinical endpoint studies. In such studies, participants must be followed until they decline to disease or death while being treated with a particular therapy compared to a placebo or a standard therapy. If there is a concensus that certain lab markers or blood tests might predict the outcome without waiting for people to suffer serious consequences, then development and approval of such lab tests are critical. Think tank participants identified one potential laboratory measure, being developed by Beckton Dickinson Laboratories, which may prove useful in assessing immune function. Using a technology commonly used to measure CD4+ cell counts, called flow cytometry, it may also be possible to look for the loss
and/or return of specific immune responses.
Increases in measures of immune activation have long been noted as HIV disease progresses. This activation may interfere with immune function as well as increase HIV replication. Studying therapies that slow this immune activation are needed. A few studies are already ongoing, including a study of cyclosporine-A at VirX, and a study of radiation therapy at the Gladstone Institute, both in San Francisco. Moreover, it was recommended that studies of the potential anti-HIV drug, mycophenolate (CellCept) evaluate how the immune suppressive effect of this drug might be adding to its anti-HIV effect. (For more information on mycophenolate, read PI Perspective 28).
While most people with HIV are familiar with CD4+ and CD8+ cells, other cells also play key roles in initiating effective immune responses. These include antigen presenting cells (APC), which carry or present HIV and other infectious agents to CD4+ cells so that they may act to eliminate or contain an infection. A number of studies suggest that there is a defect in APC activity in people with HIV and there are some therapies that, at least in test tube studies, might enhance the function of APCs. These include CD40 ligand and flt3 ligand. Neither is currently available for use in human studies in HIV and activist pressure is needed to accelerate the sponsor's interest in testing these strategies against HIV disease.
A number of other strategies which have not been studied in the setting of HIV need to be evaluated, including:
Interleukin-2 (IL-2) has been studied in people with early and middle-stage HIV, but not adequately studied in people with advanced stage HIV disease.
Interleukin-7 (IL-7), which might enhance the function of the thymus, an important organ for new T cell development (including CD4+ and CD8+ cells).
Interleukin-15 (IL-15) may increase CD4+ cell counts, similar to what has been seen with IL-2 therapy, but perhaps without the serious side effects seen with IL-2 therapy.
Destruction of macrophages: This may lead to reconstitution of new and more functional macrophages. Macrophages are APCs which can become infected by HIV. Destruction of infected macrophages was the goal sought in early years of the epidemic with the drug trichosanthin, more popularly known as "compound Q." While the drug itself is no longer under study, the strategy behind it remains valid.
Alloimmunization includes injecting someone with another person's cells to trigger an immune response. A number of researchers propose, and preliminary observations suggest, that this approach may enhance immune responses against HIV.
For more information about these approaches, others aspects of Project Immune Restoration and a full report from the recent IRTT, read Project Inform's Project Immune Restoration Discussion Paper.
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Important note: Information in this article was accurate in April 2000. The state of the art may have changed since the publication date.
