The Treatment Action Group and the American Foundation for AIDS Research held a groundbreaking scientific workshop 2/27-3/1 on clearing lingering reservoirs of HIV from patients on highly active antiretroviral therapy (HAART). The following are highlights from the meeting. A full report of the conference will be available soon. Gregg Gonsalves, who organized the scientific think tank on behalf of TAG, prepared this brief overview of the meeting.
The Central Nervous System as a Reservoir for HIV
The central nervous system (CNS) is one of the least understood reservoirs for HIV and may have an important role in the persistence of HIV infection in patients on HAART. The CNS is seeded by virus early in the disease. In monkey studies, HIV's cousin, SIV, appears in the CNS within two weeks after infection. The CNS is also a site partially sequestered from immune surveillance and the action of many antiretroviral drugs by the blood-brain barrier. There are many unanswered questions about the role of the CNS in HIV disease:
How will the answers to these important questions be resolved? One of the primary difficulties in understanding the role of the CNS in viral persistence is the inability to collect and study CNS tissue from people with HIV infection. Researchers at the TAG/AmFAR think tank called for the National Institutes of Health to establish a new tissue repository that would collect brains from patients with HIV infection who have died from other causes. Similar brain banks have been established for other neurological conditions, including Alzheimer's disease and schizophrenia. The participants in the conference also called for the development of antiretroviral drugs and adjunctive therapies that will penetrate the blood brain barrier.
Antigen Presenting Cells as a Reservoir for HIV
The macrophage is an important reservoir for HIV infection. These cells can maintain a productive infection with HIV without being killed and have a long life span. These cells may also provide a lingering reservoir for HIV under HAART because many protease inhibitors may achieve less than 99% viral inhibition in chronically infected macrophages. There are many unanswered questions about the role of macrophages in HIV infection:
There may be the opportunity to use adjunctive therapies to clear virus from this compartment. The Immunex Corporation is investigating the use of granulocyte-macrophage colony stimulating factor (GM-CSF) for this purpose. GM-CSF (and also tumor necrosis factor (TNF) and interleukin-12) stimulates macrophage reproduction, essentially "unmasking" the cells for recognition and destruction by the immune system.
T-Cells as a Reservoir for HIV
The role of T-cells in the persistence of HIV infection under HAART has been the subject of intense investigation over the past few months. Recent studies of people on HAART have shown that although productively infected T-cells are killed relatively quickly after the initiation of therapy, resting T-cells harbor infectious virus which is not likely to be cleared from patients for many years, if at all. In order to further dissect the fate of these latently infected resting T-cells, participants in the meeting called for the development of non-invasive technologies which would allow investigators to track these cells without requiring extensive biopsies of lymph nodes and other tissues.
Several investigators discussed ways of expediting the clearance of latently infected resting T-cells. There are currently two possible approaches to this problem. The first involves activating these cells using antibodies directed to the T-cell receptor or cytokines that activate T-cells. Once these cells are activated and begin to produce virus they become a target for elimination by the immune system. The second approach involves boosting immune responses to the virus which might allow clearance of infected cells by cytotoxic T-cells. Immune responses to HIV generally weaken in patients chronically infected with HIV on HAART. It may be possible to use HIV vaccines to boost the immune response in these patients. While the initial immune response to the virus in early HIV infection is not successful in clearing the billions of virions present at this stage of disease, a reinvigorated immune response may be able to clear the substantially fewer viral particles present in patients on HAART.
The Thymus, the Genital and the Gastrointestinal Tract
Along with the CNS, the thymus and the testes are relatively isolated from immune surveillance and the action of antiretroviral drugs by a tight barrier of endothelial or epithelial cells. T-cells, macrophages and dendritic cells in the thymus are infected with HIV. This site may have particular importance in children infected with HIV because the thymus generally atrophies and shrivels away by early adulthood. There is little known about the fate of infected cells in the thymus in patients under HAART. Once again, there is a dire need for tissue samples of thymus from children infected with HIV on HAART to resolve the question of whether or not this site is an important reservoir for HIV.
The gastrointestinal mucosa is the largest lymphoid organ in the body. It also has the largest concentration of macrophages and is the busiest site for cell trafficking in the body as well. The gut is a prime site for HIV replication because of its important role in the immune system. In patients on HAART, the pathology of the gut has generally mirrored that of the lymph nodes: productively infected cells expressing RNA are rapidly cleared from this site with latently infected, resting T-cells expressing HIV DNA remaining.
In the face of criticism that the National Institutes of Health (NIH) has unfairly favored certain diseases -- particularly AIDS -- in its yearly allocation of research dollars, TAG Policy Director Gregg Gonsalves traveled to Washington, D.C. early last month with the charge of defending research priority-setting mechanisms at the agency. Gregg offered up AIDS as a model of how patient advocates can get involved in the research decision-making at the NIH and asked other disease groups to come together and work for increased funding for biomedical research as a whole. Gregg had been asked to address the Academy of Sciences' Institute of Medicine (IOM) in order to aid in its preparation of a report on how the NIH decides where to spend its money. Following is a transcript of that testimony.
AIDS provides both the best and worst case scenario for research priority setting at the National Institutes of Health. Let's start with the good news first. The AIDS community through our vigorous advocacy efforts has become a respected partner with the NIH in shaping AIDS research policy. Representatives of communities affected by AIDS are participants in all areas of priority setting. We are part of decision-making bodies for the NIH's various AIDS clinical trials networks. We sit on the advisory councils of various NIH institutes and offices. We participate in the peer review process for several AIDS research programs. We are regularly consulted by program officers at the NIH, division and institute directors, the director of the Office of AIDS Research and the NIH director himself on AIDS research matters. I think that officials at the NIH and members of the AIDS community would agree that our collaboration has been good for AIDS research.
In the area of clinical research, we have helped to design studies so they better reflect the needs of patients, making them easier to enroll and retain participants. We have helped focus attention on research topics that once received less than necessary notice by the NIH: opportunistic infections and cancers. In the area of basic research, we have been able to act as a liaison between basic researchers and the NIH on many important issues, including making the case for increased support for investigator initiated research, greater and easier access to patient samples from clinical research and epidemiological cohort studies and to non-human primates through the Regional Primate Research Centers.
Congress' role in helping to shape AIDS research priorities at the NIH has been important and valuable too. In the early years of the epidemic, it was Congress that took the leadership role in making AIDS and AIDS research national priorities. It was Congress that pushed for significant increases in AIDS research funding, authorized important AIDS research programs and highlighted problems in AIDS research at the NIH. More recently, in 1993, Congress restructured the AIDS research program at the NIH giving the Office of AIDS Research a leadership role over the disparate AIDS efforts at the NIH's 24 institutes and centers. That restructuring led to a full review of the NIH's AIDS research program by the OAR that found significant strengths, but also major flaws in the NIH program. The NIH is now in the process of responding to the recommendations of the OAR panel.
While patient advocates and Congress have filled a valuable role in AIDS research priority setting at the NIH, there are examples where our good-intentioned contributions have not been so useful. We have sometimes pushed for funding in Congress for specific research topics only to see the money for these cherished areas taken from other important AIDS programs at the NIH. Congress has also sometimes been at loggerheads with the extramural scientific community and the NIH, bungling its way unwanted into the research priority setting process. Only a few years ago, Congress tried to roll back the authority it had granted the OAR over the NIH AIDS research program in 1993 -- only to be met with vociferous opposition from AIDS researchers, AIDS advocates and NIH Director Harold Varmus. Congress still stands in the way of important AIDS research by imposing content-based restrictions on HIV prevention research and bans on research using fetal tissue. In the most gross violation of its role, Congress has, on one occasion, overruled peer review decisions and reinstated funding for AIDS research projects denied by the NIH.
Patient advocates and Congress have had a role in shaping AIDS research priorities at the NIH, but the primary responsibility for this job has been -- and should be -- vested in the scientists at the NIH with extensive input from the extramural scientific community. How have NIH scientists fared in setting AIDS research priorities? Earlier I mentioned the review of the NIH's AIDS program commissioned by the OAR, which was carried out by a panel of over one hundred extramural scientists and patient advocates and led by Dr. Arnold Levine of Princeton University. What did that report find? Again, the NIH AIDS program came in for a great deal of praise in the report, but there were several startling discoveries and major criticisms:
The NIH has rectified many of the problems in the AIDS research program identified in the Levine report. Some of the major recommendations for change, however, have yet to be implemented. It is up to patient advocates and the extramural scientific community to follow the progress of the implementation of the Levine report and to press NIH officials when that progress is lagging. Setting research priorities at the NIH is a delicate balancing act. At least in AIDS, after fifteen years of research and ten years of advocacy, I believe it has become a tenuous and mostly successful partnership between NIH officials, extramural scientists, patient advocates and Congress. It has been the push and pull between all of these parties that has kept AIDS research going in the right direction.
Where do we go from here? In research on other diseases, the NIH should learn from its experiences in AIDS and more fully integrate patient advocates and extramural scientists into the priority setting process. Last year, I had the chance to meet with the (now former) President of the American Heart Association, Dr. Jan Breslow, of Rockefeller University. He told me that he had extreme difficulty in getting the NIH to listen to the AHA's recommendations on heart disease research. Why is the NIH refusing to listen to a prominent member of the extramural scientific community and the leader of the premier national advocacy organization for research on cardiovascular disease?
Finally, we are here today because Congress has asked the Institute of Medicine to assess the process of priority setting at the NIH. Let's be clear about why Congress has suddenly become interested in this issue. For the past several years, a few vocal patient advocacy groups have been going around Capitol Hill pitting one disease against another in the quest for scarce research funding. They have all but asked Congress to step in and begin to slice up the NIH pie according to a crude calculus which would simply allocate research dollars according to the number of deaths from a given disease in a given year. Eloquent criticisms of this misguided proposal have been made by many people, including the chairman of this committee, Leon Rosenberg; Kenneth Shine, the President of the Institute of Medicine; and John Suttie, the President of the Federation of American Societies for Experimental Biology. I think it is worth quoting Dr. Suttie's testimony before Congress last May in some length:
"First, simple, quantitative measures, while useful, are inevitably incomplete, often flawed and subject to manipulation. For example, NIH's own tables regarding spending levels for various diseases have no common definition of direct and indirect spending which makes it specific to a particular disease. No single quantitative comparison -- expenditures per case, death or years of life lost, or economic or budgetary impact -- works across all diseases for allocation purposes. None takes into consideration the non-quantifiable element such as the degree of human suffering. Second, basic research, recognized universally as the foundation of most advances in disease-specific research, will inevitably suffer in a politically based system of allocating scarce dollars. If Congress assumes a more dominant role in allocating funds, we are concerned that it will be difficult to support untargeted, long-term investments in basic science. Third, earmarking by disease is not necessarily the way to produce breakthroughs in a particular area, since research in one area often produces unpredictable results that find specific use in another. Fourth, it is important in looking at Congress' role in allocating funds to remember the adage, 'No good deed goes unpunished.' Without a thorough understanding of the impact of an increase in funding in a particular disease or program area will have over multiple years -- which is seldom available to Congress -- an increase in one area may do substantial damage to other equally deserving programs."
I hope that Congress will reject the divisive tactics of some of my colleagues and continue to rely on the guidance of the NIH director in setting funding levels for agency's institutes and centers. Allocation decisions are never easy, but the NIH has the right mix of expertise to make these choices. The NIH director -- with input from other NIH scientists, extramural researchers and patient advocates -- is best able to judge not only the human and economic costs of any given disease, but the scientific opportunities and challenges facing both disease-specific and more general basic biomedical research. Today, we challenge other disease advocacy groups to work with us to see that the NIH gets a bigger share of the federal budget.
Even though Congress appears to overwhelmingly support biomedical research, our current funding for the NIH is frighteningly inadequate. Researchers across all fields of study are spending more time struggling for support for their work. All the while, the best young minds in this country are being discouraged from pursuing a career in the sciences. What's worse, our lack of sufficient national support for biomedical research is hampering the search for better treatments for all diseases. We shouldn't be asked to choose whose life gets saved. Each life lost to human disease is precious and irretrievable. Research on all diseases benefits when the NIH's budget increases as a whole.