HEALTH

ANTHONY S. FAUCI

The Scientific Agenda for AIDS

NIH must balance creativity with control, basic research with applied, and urgency with rigor.

The magnitude of the Acquired Immune Deficiency Syndrome (AIDS) epidemic and the urgency to develop a treatment and vaccine place enormous demands on scientific research. Planning and managing this research raises a host of difficult policy decisions: how to achieve a proper balance between government-directed research and investigator-initiated research; how to coordinate a national effort without stifling creativity; how to continue to encourage basic, nondirected research that may have no immediate clinical impact but forms the foundation for future achievements; and how to balance the design of scientifically sound clinical trials against the public desire to have drugs quickly available to large numbers of patients.

Responsibility within the federal government for coordination of basic and clinical research rests primarily with the National Institutes of Health (NIH) AIDS Executive Committee. The NIH research strategy for AIDS follows the traditional approach used by researchers confronting any new disease. The primary components of this approach are: (1) epidemiology (the study of the distribution of AIDS in the population) and natural history (the patterns of evolution of disease); (2) the identification and characterization of the etiologic agent (the virus that causes AIDS); (3) delineation of the mechanisms of pathogenesis (the mechanisms whereby the virus destroys the immune system); (4) the development and testing of antiretroviral therapies, therapy for opportunistic diseases, and immunologic reconstitution (building up of the body's defenses); and (5) development and evaluation of vaccines.

Critical building blocks for the current AIDS efforts were supplied by the National Cancer Institute's (NCI) research program on cancer virology, immunology, drug development, and infectious complications of cancer, which began in the early 1970s with the federal government's War on Cancer. Similarly important were National Institute of Allergy and Infectious Diseases' (NIAID) studies of basic mechanisms of immune system function; basic and clinical virology, microbiology, and infectious diseases; molecular biology; animal retrovirology; and programs to develop antiviral therapies and vaccines. In addition, the basic science efforts of virtually all of the NIH institutes have been essential to the the research foundation of the present federal AIDS effort.

The cause and path ofAIDS

A variety of mechanisms, from pure surveillance to studies of the relationships of the various factors that determine frequency and distribution of disease, have contributed to a detailed description of the epidemiology and natural history of AIDS. The NIH's function in this area is complementary to the activities of the Centers for Disease Control.

Some of the most fundamental observations concerning etiologic agents and pathogenesis have sprung from studies of the natural history of AIDS and other infectious diseases. And although epidemiologic studies in the United States and abroad were initially undertaken to define affected populations and provide clues to the cause of the disease, they continue to provide valuable insights into how the human immunodeficiency virus (HIV) destroys the immune system, the nature of the immune response to the virus, the biological characteristics of the virus (such as mutation rates), and possible cofactors in the initial infection as well as in the progression to clinical disease.

Within three years of the recognition of AIDS, Dr. Luc Montagnier of the Institut Pasteur in France and Dr. Robert C. Gallo of the National Cancer Institute (NCI) identified the HIV as the cause of AIDS. Their work was based on prior research on the role that specific populations of T lymphocytes play in immune function and on studies of another human retrovirus, the human T lymphotropic virus-I that is known to affect T lymphocytes. This discovery spurred an accelerated effort that led to the development of HIV blood-screening tests, one application of which is to safeguard blood supplies. Once the virus had been identified, an equally intensive effort was begun to clone and sequence the viral genes in order to delineate their specific functions as well as the functions of the proteins encoded by these genes. Three crucial purposes are served by this effort: to predict how to interfere with specific functions of the virus; to provide a basis for the development of targeted antiretroviral agents; and to provide a framework for vaccine development.

The fact that HIV is a retrovirus complicates the development of effective therapies and vaccines because a retrovirus has the unique capability of integrating its genes into the genetic machinery of the host cell. Consequently, HIV can remain in a dormant or latent state, shielded from attack by most drugs or immunologic mechanisms. The development of therapies for viral diseases has always been difficult. Antiretroviral therapy may prove to be even more elusive.

The attack on the immune system

HIV attacks the T4 helper lymphocyte, which is fundamental to the operation of the entire immune system. The implications of this are enormous. The virus quickly immobilizes the very host defense component that is programmed to defend the body against microbial invaders, particularly other viruses. More recent research reveals that the brain is also a target of HIV, and such neuropsychiatric manifestations as memory loss and dementia are major clinical consequences of HIV infection.

An HIV-infected individual may remain totally asymptomatic for several years before progressive immunologic deterioration leads to the opportunistic infections and/or cancers that constitute the diagnosis of AIDS. Recent data indicate that approximately 20 to 30 percent of asymptomatic HIV-infected individuals will develop AIDS within five years of infection. However, it has also been demonstrated that up to 90 percent of infected individuals will experience some form of immunologic deterioration within five years despite the fact that the majority will remain asymptomatic. Researchers need to understand the mechanisms of immune cell destruction during this extended period of time.

Scientists have learned through laboratory experiments in which cells are infected with HIV that certain cells survive that are either latently infected (integration of viral DNA into cellular DNA without virus production) or chronically infected (low-level virus production). They have also discovered that a variety of activation signals, including other viruses as well as substances produced by cells during a normal immune response, contribute to the conversion of a latent or chronic infection to a productive one.

Although enormous progress has been made in delineating the mechanisms of pathogenesis of HIV infection, these studies have also revealed an extraordinary complexity in the process of infection and cell killing. Despite the fact that scientists know precisely what the receptor for the virus is, what cells the virus infects, and what happens to the host when the T4 cells are eliminated, there are still many unanswered questions in the pathogenesis of HIV infection. For example, scientists do not know how HIV actually kills the T4 cells in the body.

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Thus, despite the fact that this is a human disease that is well studied, a number of scientists feel strongly that animal models must be developed for the study of pathogenesis. A sound animal model will allow for studies aimed at precisely delineating the mechanisms involved in the pathogenesis of HIV infection from the initial exposure of the animal to the virus up to the actual destruction of the immune system and the deterioration of central nervous system function. In this regard, simian T lymphotropic Virus-III infection in the macaque is showing great promise as an animal model. On the basis of the wealth of information already gained from human studies as well as the potential advantage of a sound animal model, NIH supports research on pathogenesis in humans and the concurrent development of animal models.

In order to generate new approaches and strategies to better understand how the virus is activated from a latent state, kills the T4 lymphocytes, and causes progressive disease, NIH has expanded its support for investigator-initiated research in these areas. Other programs are intended to foster collaborative multidisciplinary interaction among researchers from aeademia, industry, and government. An example of this is the Programs of Excellence for Basic Research on AIDS, which will be established by NIAID within the coming year to coordinate basic science studies on immunovirology, and molecular biology of HIV.

Finding and testing drugs

Finding safe and effective therapeutic agents for HIV is an extraordinarily difficult task. Because viruses are intimately associated with cells during their life cycles, drugs that interrupt the viral life cycle often damage the host cells as well. Only a handful of antiviral drugs have ever been approved, and none of these actually cures the disease. Retroviruses present an even greater challenge because they actually become a part of the host cell's genetic machinery.

NIH is pursuing two approaches in the search for antiretroviral drugs: screening large numbers of existing compounds and initiating targeted drug development The initial emphasis was on screening existing compounds because it offered the best hope of near-term success and was already being implemented for other diseases. In collaboration with the Burroughs-Wellcome Company, NCI scientists uncovered the anti-HIV properties of azidothymidine (AZT), which inhibits the activity of the HIV reverse transcriptase, an enzyme essential for the replication of the virus. In September 1986, when it became apparent that AZT was effective in certain AIDS patients, NIH and Burroughs-Wellcome quickly set up a system to distribute the drug to all patients who would benefit from it.

In a collaborative effort between NIAID and NCI, existing institute mechanisms were used to distribute the drug free of cost to nearly 5,000 patients in only 90 days. By March 1987, FDA licensed AZT for general distribution.

Thus, NIH was able to help make the drug available in a short time to a significant number of patients. AZT is currently the only Food and Drug Administration (FDA)-licensed drug for AIDS patients and HIV-infected individuals who have markedly reduced T4 lymphocyte counts. Because AZT offers only limited relief, is not effective for all AIDS patients, and is actually toxic for a significant proportion, the search for other AIDS drugs continues.

The establishment of detailed models of the biological and structural properties of the virus made it possible in 1986 to begin a targeted development effort to complement drug screening. Targeted drug development uses the information gained about the specific properties of HIV to design agents that can specifically interfere with the life cycle of the virus or with a specific structural component of the virus. This can be a painstaking and expensive process, which may take years to come to fruition and which requires the talents of virologists, molecular biologists, structural biologists, physical chemists, pharmacologists, and crystallographers, among others. To broaden expertise beyond the immunologists and virologists who have been the predominant participants in AIDS research, NIH earmarked $10 million in 1987 to bring intramural investigators with varied scientific interests into AIDS research and, through the National Institute of General Medical Sciences, to establish six program project grants to stimulate the organization of multidisciplinary extramural research group that would focus on studies related to the structural biology of HIV.

NIH also recognised that a multidisciplinary approach to drug development could benefit from the interaction of a consortia of investigators from industry, academia, and government. Adopting a process used in development of anticancer drugs, NCI and NIAID funded five National Cooperative Drug Discovery Group in 1986 to develop new therapies for AIDS. NIAID recently funded an additional 11 groups. All together, these groups represent an expanded, coordinated effort to use the capabilities of academic institutions, pharmaceutical companies, biotechnology and bioengineering companies, NIH intramural scientists, and international organizations to cooperatively develop anti-HIV drugs. The discovery groups represent the core and the major component of the NIH-sponsored program for development of drugs targeted at HIV infection.

A coordinated, scientifically sound approach to treatment involves a policy not only for drug development but for drug testing as well. To assist the scientists working on AIDS drug development, NIH has established two advisory groups to review data on proposed experimental drug treatments from any source. The AIDS Decision Network Committee, administered by NCI, sets priorities for drugs to be developed preclinically, and the AIDS Clinical Drug Development Committee, administered by NIAID, establishes priorities for clinical trials. Each has representation from NIAID and NCI staffs as well as from the extramural scientific community.

Promising drugs emerging from screening or development programs are tested at the newly created, NIAID-funded AIDS Treatment Evaluation Units. As of November 1987, 23 clinical trials were under way at 19 evaluation units situated in medical centers throughout the country.

In addition, a mechanism is needed to complement drug evaluation with basic multidisciplinary scientific approaches and community outreach. On September 30, 1987, NIAID announced funding of 17 Clinical Studies Groups, located in 10 states and the District of Columbia, to perform AIDS treatment studies, basic research studies, and outreach. Through the study groups, NIH can make promising AIDS therapies available to larger numbers of patients in a much wider geographic area than has previously been possible. The evaluation units and study groups will comprise a coordinated computer-linked network that provides significant research advantages. For example, it will facilitate collaborative studies among institutions, thereby accelerating the drug evaluation process.

Clinical trials of promising agents are also proceeding in NCI and NIAID intramural programs. One highly experimental approach is immunologic reconstitution—rebuilding the immune system that the AIDS virus has destroyed. This approach, together with specific antiretroviral therapy, provides a potential two-pronged attack: suppressing virus replication at the same time that the damaged or destroyed immune system is being rebuilt. Researchers at NIH have conducted clinical trials with interleukin-2 and other biological response modifiers (synthetic or biological reagents that could boost immune response) and have performed bone marrow transplantation combined with antiretroviral therapy. It is too early to determine the efficacy of the latter approach, and scientists are planning further investigation in this area.

A program cannot expand from a $3 million to a $500 million effort in five years without also bringing in new people and expanding the infrastructure.

Protection from AIDS

Developing an AIDS vaccine will be particularly challenging because of the mechanism of HIV infection and because scientists still do not fully understand the nature of an effective immune response. In developing vaccines for diseases such as polio and influenza, scientists could study individuals who recovered from the disease without treatment, and then use their natural immune response as a model for a vaccine. No such model exists for HIV because no one has yet recovered from the disease.

In the past, decades generally passed between identification of the cause of a disease and the development of a vaccine. Although scientists identified HIV as the cause of AIDS extremely quickly, it is unrealistic to think that a vaccine can be developed with the same unprecedented speed. Even though new recombinant DNA technology can speed vaccine development, the nature of HIV, the existence of multiple strains of the virus, and the complexity of the body's immune response to this organism make this a very difficult problem. In addition, it would be logistically impossible to adequately test a candidate vaccine for safety, immunogenicity, and efficacy in a period of a few years.

Also complicating the development of an HIV vaccine is the lack of an adequate animal model in which to test candidate vaccines, an essential step in conventional vaccine studies. The chimpanzee is the only animal at this time that can be infected with HIV, but no chimpanzee has, so far, developed AIDS. Nevertheless, experimental vaccines are being tested on chimps. In addition, researchers are testing candidate vaccines for a related animal retrovirus of monkeys— simian immunodeficiency virus. No successful vaccines have been found in either case.

NIH is supporting several approaches to vaccine development: whole killed virus, purified natural products of the virus, synthetic preparations of parts of the virus, recombinant DNA products, recombinant vaccinia virus containing parts of the HIV genome, and anti-idiotype (antibodies generated against antibodies to the virus). The ability of HIV to integrate into the cell's genetic machinery means that the use of a whole killed virus risks introducing viral genetic material into the host cells, which might trigger tumor development or other undesirable side effects. A whole-virus approach may be necessary, however, because subunit vaccines (protein components of the virus rather than the whole virus) may elicit protective immunity against only the original strain of virus used to make the vaccine and not against the numerous other strains of HIV to which the vaccinated person might become exposed.

A concentrated effort is now under way to develop vaccines through recombinant DNA technology. Several of these candidate vaccines are already being studied in the laboratory and in animal models. In fact, FDA has approved two candidate vaccines for phase I testing in humans to determine safety and immunogenicity. In order to encourage innovative approaches to new vaccine products, NIAID in early 1988 will fund National Cooperative Vaccine Development Groups to foster collaboration among academic research institutions, industry, and government.

Vaccine Evaluation Units, which were established at six universities by NIAID to test vaccines for a variety of diseases such as hepatitis B, influenza, and pneumococcal pneumonia, will assist in future tests of potential AIDS vaccines. Liability issues may complicate vaccine testing in these units if the institutions are unable to obtain insurance for the trials. This latter issue is of particular importance, and legislative inter-vention may be required to resolve this problem, which is a potentially major impediment to the conduct of vaccine trials in general and those involving HIV in particular.

One additional obstacle to the development of an AIDS vaccine is the actual testing of vaccines for efficacy. Because AIDS is a fatal disease, it is obviously unethical to deliberately expose anyone to HIV. The only way to prove efficacy, therefore, is to administer the vaccine to a large number of people who are at risk for developing HIV infection and who can be followed for extended periods of time. The currently low incidence of new HIV infection in populations at risk, such as male homosexuals, in the United States means that thousands of people would have to be enrolled in a vaccine trial. Furthermore, ethical considerations would require that participants in the trial be adequately instructed in how to avoid infection with HIV, making it more difficult to prove efficacy of a vaccine.

The alternative may be to test a vaccine in another country where the incidence of HIV infection is much higher and where the efficacy of a candidate vaccine can be more readily demonstrated. Vaccine testing in other countries can be complicated, however, by such considerations as the differences in strains of HIV and the social and political structures of the country.

New directions, new needs

The urgency of the AIDS crisis forced NIH to modify its traditional practice of letting investigator-initiated research guide scientific progress. Soon after the discovery of AIDS, NIH decided to assume direction of some areas of AIDS research that may not have been taken up by investigators due to either the lack of a readily apparent yield or the lack of scientific interest. NIH has funded a large number of government-directed contracts and issued many specific requests for grant applications in the first few years of the AIDS epidemic.

More recently, NIH has allocated a greater proportion of its funds to collaborative agreements, thereby allowing NIH program staff to act as facilitators for projects of investigator-initiated research. These early efforts in directed research have sparked the interest of many investigators who are now presenting new approaches to difficult problems in their own investigator-initiated research.

As more investigators become interested in AIDS research and more institutions develop the capability of treating AIDS patients, the program is shifting back toward investigator-initiated research in many areas. The treatment evaluation units, for example, are being converted from contracts to cooperative agreements, and the new Clinical Study Groups are being established at the outset as cooperative agreements.

A program cannot expand from a $3 million to a $500 million effort in five years without bringing in new people and expanding the infrastructure. There is a pressing need for scientists trained to do AIDS research. Providing research funding will do little good unless there are skilled researchers to do the work. NIH can provide training, but at present the total number of trainees that can be supported by NIH in all fields is fixed. Rather than divert resources from the training of investigators in other critical areas, NIH needs new funds and authority to train additional AIDS researchers.

Another critical need involves AIDS research facilities—upgraded as well as new—at NIH and other research institutions. Needed facilities include special laboratories for working with the virus and clinical facilities for drug and vaccine evaluations.

The fatal nature of AIDS puts pressure on the scientific community to loosen the standard procedures for evaluating drugs by making experimental drugs available sooner and more widely. NIH maintains that the decision to enter a drug in a clinical trial should continue to depend on the scientific evaluation of a drug's promise, not on unsubstantiated claims by the manufacturer or others. Such claims merely serve to create false hope among potential drug recipients and to create undue pressure to test potentially harmful agents, ultimately diverting resources and energy from the testing of truly promising agents. Because of the risks inherent in any new drug, the standard practice is to minimize the number of participants in a test The evaluation of AZT, for example, involved only 282 individuals.

Central to NIH's policies on AIDS is support of basic research. Even as scientists focus on such applied research as clinical trials of promising drugs and new vaccine products, NIH continues to foster basic research through the development of Programs for Excellence in Basic Research on AIDS as well as through the traditional investigator-initiated awards in basic biomedical research. This policy stems from the recognition that the advances in AIDS research that have been made to date rest on the firm foundation of many years of basic research. This base is not only essential to our efforts in AIDS research, but will also be crucial to our scientific ability to meet future challenges to the health of our nation and the world.