NIH 1998 Almanac/The Organization/NIAID/       National Institute of Allergy & Infectious Diseases: Research Programs Investigators at universities, hospitals, and private research institutions throughout the country receive support through grants and contracts administered by the Division of Microbiology and Infectious Diseases; Division of Allergy, Immunology, and Transplantation; and Division of Acquired Immunodeficiency Syndrome. Division of Microbiology and Infectious Diseases The Division of Microbiology and Infectious Diseases supports extramural research to control and prevent diseases caused by virtually all infectious agents except HIV. DMID supports a wide spectrum of projects spanning basic biomedical research, such as studies of microbial physiology, to applied research, including the development of diagnostic tests and the conduct of clinical trials to evaluate experimental drugs and vaccines. Current areas of emphasis include emerging infectious diseases, hepatitis C, malaria, and foodborne diseases. Viral Diseases. Viruses are the major cause of infectious diseases requiring medical care in the United States. The cost in dollars or in days lost from work is estimated to be in the billions each year. Following an initial infection, which may occur without symptoms, many viruses persist in the body for life and may lead to serious medical problems, including immune complex diseases, degenerative diseases, cancer, heart disease, and liver disease. NIAID supports basic studies of virus structure, replication, gene regulation and evolution as well as studies in animals and humans that investigate the viral epidemiology, pathogenesis, and host immune response. This research program provides the foundation for the development of vaccines and antiviral therapies. Respiratory infections are the major cause of acute illness in the U.S. NIAID supports development and testing of vaccines against virus-caused respiratory diseases such as influenza and respiratory syncytial and parainfluenza viruses, which cause the majority of croup, bronchitis, and pneumonia in infants and children. Viral hepatitis caused by hepatitis A, B, C, D, and E is another group of diseases with a major impact on health worldwide. In some parts of the world, hepatitis is the primary cause of liver cancer. Each year in the U.S., more than 600,000 new viral hepatitis infections occur which, when acute, can be debilitating and costly. Chronic disease resulting from infection with hepatitis B, C, and D is an even greater problem. Medical costs for chronic hepatitis are between $1 and $2 billion a year. NIAID-sponsored studies focus on virology, molecular biology, immunology, pathogenesis, development of antivirals, animal model development, natural history, vaccine development and clinical trials. Vaccines have now been licensed for hepatitis A and B. Diarrheal diseases caused by viruses are particularly a problem among infants in developing countries. Experimental vaccines against rotaviruses--a major cause of infant diarrhea worldwide--have been extensively tested in children and infants. One vaccine developed in NIAID intramural laboratories is expected to be licensed for use in the U.S. Although there have been reports of possible viral associations in chronic fatigue syndrome (CFS), no specific causative role for any virus has been demonstrated. To explore possible causes of CFS, the institute has funded CFS Cooperative Research Centers to provide a multidisciplinary approach to CFS research by conducting basic science and clinical investigations on CFS. NIAID also supports scientists who are studying the possible immune system dysfunction, exercise-induced fatigue in CFS patients, as well as other aspects of CFS pathophysiology, and its epidemiology. Development of Antiviral Drugs. Because many drug sponsors do not have access to comprehensive antiviral screening facilities, NIAID has established screening facilities for the in vitro evaluation of an experimental compound’s activity against hepatitis B virus, human herpes viruses--herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), and Epstein-Barr virus--and the respiratory viruses--influenza types A and B, respiratory syncytial virus, parainfluenza, measles, and adenovirus. This service is available to any scientist with a potential antiviral compound and an inability to test it. NIAID supports drug evaluation studies, preclinically in animal models of human viral infections and in human clinical trials. Institute-supported investigators participating in the Collaborative Antiviral Study Group test drugs for treating herpes encephalitis, neonatal herpes, hantavirus pulmonary syndrome, symptomatic congenital CMV infection, chronic hepatitis B and C virus infection, flu, and respiratory syncytial virus infection. Other investigators have evaluated interferons for human papilloma infections such as genital warts. Bacterial Diseases. In the last decade, several bacterial diseases have emerged as new or recurring threats to the health of people in the U.S. and elsewhere, including Lyme disease, ehrlichiosis and tuberculosis (TB). Lyme disease, first recognized in the early 1980’s in this country, is caused by a bacterium transmitted to humans by certain ticks. It has emerged as a significant problem in the northeast coastal areas, among others. NIAID spearheads NIH studies on Lyme disease, supporting research focusing on pathogenesis, improved therapies, better diagnostic tests, and vaccines. NIAID also supports research on ehrlichiosis, a life-threatening tick-borne infection transmitted by the same Ixodes ticks that carry Lyme disease, NIAID-supported investigators are trying to determine whether coinfection with ehrlichiosis interferes with the diagnosis and pathology of Lyme disease. Tuberculosis, a serious disease once thought to have been conquered in the U.S., is reemerging in certain American cities. TB has a staggering impact worldwide, since one-third of the world’s population is infected with the TB bacterium. Although most people who are infected never develop active TB, those with weakened immune systems--especially those infected with HIV--are particularly vulnerable to active TB disease. Each year 8 million people world-wide develop active TB, and 3 million die. With appropriate antibiotic therapy, TB usually can be cured. In recent years, however, drug-resistant cases of TB have increased dramatically. Particularly alarming is the increase in the number of persons with multidrug-resistant TB caused by bacterial strains resistant to two or more drugs. Even with treatment, the death rate for multidrug-resistant TB patients is 40 to 60 percent. As the lead institute for studies on TB, NIAID supports basic research into its biology; development of: new tools to diagnose TB; drugs or ways to deliver them; clinical trials of anti-TB therapies; and vaccines to prevent it. NIAID also funds research on leprosy, or Hansen’s disease, which is caused by a mycobacterium. Although treatable today, there are about 1.3 million leprosy patients requiring treatment worldwide, largely in subtropical climates. More than half a million cases are diagnosed each year. Research on atypical mycobacteria, which constitute a diverse and heterogeneous group of acid-fast bacilli that are widespread throughout the environment, is of increasing importance in light of the AIDS epidemic. These organisms rarely cause disease in healthy adults, however, they can cause serious opportunistic infections in people with impaired immune systems. Cholera is a disease caused by the bacterium Vibrio cholerae. Infection results in severe, dehydrating diarrhea that is particularly dangerous to infants and small children. In 1991 cholera reappeared in the Western hemisphere for the first time in 100 years. The epidemic has spread as far north as Mexico and is a threat to travelers to Central and South America. In 1992 a new strain of V. cholerae appeared in Asia and an area of the Bay of Bengal. NIAID supports research aimed at understanding the pathogenesis of the disease, what constitutes protective immunity, and the development of effective vaccines. Effective antimicrobial agents have significantly reduced the burden of bacterial infections, even though their usefulness is limited by increasing bacterial resistance to antibiotics and in those diseases with an onset and progression so rapid that effective treatment is difficult. NIAID supports the development and testing of bacterial vaccines for Hemophilus influenzae type b, Streptococcus pneumoniae and all causes of meningitis; pertussis (whooping cough); cholera; shigella; and typhoid fever. Hospital-associated, or nosocomial, infections have emerged in recent years as a significant health problem and cause of increased morbidity and mortality. They directly contribute to rising health care costs. An estimated 2 million hospital-associated infections occur in the U.S. each year, at a cost of more than $3 billion. Gram-negative sepsis following surgery or trauma remains the most serious threat to patients, with mortality rates ranging from 25 to 40 percent if sepsis occurs. NIAID supports studies on immune mechanisms--cellular and humoral--that protect healthy people against normal microbial flora commonly encountered every day. Another focus is the study of disturbances in resistance mechanisms in hospitalized or immunocompromised patients. Gram-negative bacteria from the gastrointestinal tract are the primary etiologic agents and many have become resistant to antibiotics. Hospital acquisition and transmission of methicillin-resistant staphylococci, Candida, enterococci, and antibiotic-resistant gram-negative bacteria are important areas of investigation. The recent emergence of Staphylococcus aureus exhibiting intermediate levels of resistance to vancomycin (the antibiotic reserved for treating infections due to multidrug resistant strains) has prompted NIAID to initiate an integrated research plan to address this important problem. The interplay of bacterial toxins such as lipopolysaccharide and staphylococcal toxic shock toxin with host serum and cell components can result in fever, shock, and death. NIAID is investigating the underlying mechanisms of shock and its control and prevention. Fungal Diseases. Severe, sometimes life-threatening systemic infections caused by fungal organisms have long been recognized in all age groups and in all parts of the U.S. Treatment requires prolonged administration of relatively toxic drugs and is sometimes ineffective, even in the otherwise healthy patient. Fungal infections are increasingly recognized as a major cause of morbidity and mortality in patients with impaired immune defenses. NIAID supports research on medically important fungi such as Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus. Antimicrobial Drug Development. As promising new antibacterial and antifungal agents are developed, they must be critically evaluated for safety and efficacy in humans. NIAID selects for trial licensed and unlicensed drugs that the pharmaceutical industry is unlikely to test further in humans, even though the drugs may show considerable clinical promise. Controlled, prospective, and multicentered studies are designed to compare efficacy, safety, duration, and costs with standard chemotherapeutic agents. Currently, the institute supports trials of new systemic antifungal agents and, together with NICHD, an antibiotic trial for vaginal infections in pregnant women. Sexually Transmitted Diseases (STD). A dramatic increase in the number of new cases of STDs has occurred over the past 50 years in the United States. Gonorrhea, syphilis, genital herpes, genital warts, chlamydial infections, and pelvic inflammatory disease (PID) take an increasingly large toll emotionally, physically, and economically. Each year in the U.S. there are approximately 4 million new cases of chlamydia, 0.5 million new cases of gonorrhea and 1 million new cases of PID. Thirty million Americans are estimated to have genital herpes, and 24-40 million are thought to be infected with human papillomavirus (HPV), several types of which are causally associated with development of cervical cancer. STDs often have long-term, devastating consequences--particularly for women and children. Infertility, ectopic pregnancy, cervical cancer, increased risk of infection with HIV, and adverse outcomes of pregnacy, including fetal death, low birth weight, and congenital infections resulting in permanent physical and mental damage to infants, can result from STDs. In 1995 economic costs associated with PID alone were estimated to exceed $6 billion. Current research priorities and initiatives focus on vaccine development, the sequelae of STDs in women, behavioral research, HPV, genital ulcer disease, the development of rapid, inexpensive diagnostics, and the development of topical microbicides. NIAID conducts and supports basic research necessary to develop vaccines against all STDs including gonorrhea, chlamydial infections, syphilis, herpes, HPV infection, and chancroid. Because of the severe and disproportionate impact of STDs on health of women and infants, NIAID seeks to develop and evaluate interventions to reduce the incidence and severity of complications of PID, such as infertility, ectopic (tubal) pregnancy, and chronic pelvic pain syndromes. Furthermore, because STDs are preventable causes of adverse outcomes of pregnancy such as fetal wastage, low birth weight, and congenital infections, this area is also a priority. In recognition of the critical interplay between behavioral and biomedical risk factors for STDs, NIAID developed a program in integrated, intervention-oriented behavioral research for the prevention and control of STDs. Studies of the pathogenesis and natural history of HPV are important areas of research. The role of HPV in development of cervical dysplasia and malignancy, development of animal models of genital HPV infection, and improved methods for detection and management of HPV infection are among the research areas of interest to NIAID. The expansion of research on the pathogenesis and natural history of genital ulcer disease and on the interrelationship between these diseases and HIV is of high priority. Research on chancroid, syphilis, and genital herpes is being emphasized. Parasitic Diseases. Parasitic diseases, a world health problem, affect billions of people and are responsible for millions of deaths annually. While their principal health and economic impact is felt primarily in poor and developing countries, many parasitic infections remain endemic within the United States and can present a threat to individuals with immature or compromised immune systems or in situations where normal sanitation procedures break down. In addition, increased foreign travel by U.S. citizens as well as immigration to the United States allows importation of so-called "exotic" parasites from other countries. Several unicellular protozoa and multicellular helminths cause parasitic disease. Goals of NIAID-sponsored studies on the immunology of parasitic diseases include development of effective vaccines against malaria, schistosomiasis, leishmaniasis, and others; the intervention in the host response to prevent immunologically mediated disease processes; and the development or improvement of immunodiagnostic procedures. NIAID also supports basic research on the biochemistry and molecular biology of parasites to develop new chemotherapeutic agents or improve the efficacy of existing drugs. Development of drug resistance is a rapidly increasing problem, particularly in malaria. Application of modern biochemical and molecular technology to determine how resistance develops may reveal ways to reverse the phenomenon. NIAID supports Tropical Disease Research Units at domestic institutions to provide a stable environment for research on parasitic diseases. These programs apply relevant and innovative biomedical technology to develop new approaches to control parasitic diseases. Vaccine Development. Vaccines have virtually eliminated once common killers such as diphtheria, tetanus, and polio in the U.S. Nearly 25 major human diseases caused by infectious agents are preventable or controllable through vaccine use. Despite this success, both new and old infectious diseases continue to threaten the health of people around the world. The aim of the NIAID vaccine program is to capitalize on the extraordinary advances in molecular biology and immunology in order to improve the safety, effectiveness, and efficiency of existing vaccines and enhance the development of new vaccines. This is also the goal of the Children’s Vaccine Initiative, a global project of which NIAID is an integral part. As the lead PHS agency for vaccine research, NIAID coordinates a comprehensive program among scientists in government, industry, and academic settings. Vaccine research is conducted by NIAID scientists as well as by institute-supported investigators at research institutions, including six Vaccine Treatment and Evaluation Units. The units conduct clinical trials of candidate vaccines to determine whether they are safe, immunogenic (capable of stimulating an immune response), and effective. Research on HIV vaccines is supported by NIAID’s Division of AIDS. International Research The institute’s international research activities involve grants, contracts and intramural projects to promote scientific research on tropical and other diseases of great importance to the health of people in developing and developed countries of the world. Immediate aims are to improve means for diagnosing, treating, and controlling these diseases with the ultimate goal of disease prevention. For example, the U.S.-Japan Cooperative Medical Science Program, organized in 1965, provides an opportunity for American and Japanese scientists to cooperate in studying 10 disease-related areas of importance to the health of Asian people. In September 1979, the International Collaboration in Infectious Diseases Research Program replaced the International Centers for Medical Research and Training which had been operational since 1960. Under the program, research centers are established in tropical countries through multidisciplinary program project grants awarded to U.S. institutions. The program is designed to promote true collaboration and scientific exchange between U.S. scientists and their overseas counterparts. The program addresses infectious diseases of health importance to the host country. In 1991 NIAID established Tropical Medicine Research Centers to provide overseas facilities for the study of tropical diseases within endemic areas. Established in 1994, the Tuberculosis Research Unit (TBRU) is an international, multidisciplinary research group focused on translating basic research findings into human clinical trials with the goal of developing tools for TB control. The TBRU brings together investigators with expertise in TB pathogenesis and microbiology, immunology, diagnostics development, epidemiology, and the conduct of clinical trials at domestic and international multiple research centers. Other international activities include the NIAID-USAID Middle East Regional Cooperation Program, carried out through Jordan, Morocco, Lebanon, Tunisia, and Israel, to study leishmaniasis and hydatid disease. NIAID also coordinates studies on the immunology of infectious diseases as part of the Indo-U.S. Science and Technology Initiative. Division of Allergy, Immunology and Transplantation This division focuses on the immune system as it functions in the maintenance of health and as it malfunctions in the production of disease. It encompasses basic and clinical research. Basic research is supported in 1) immuno-biology and immunochemistry and 2) immunogenetics and transplantation immunology. Clinical research is supported in asthma and allergic diseases, and immunologic diseases and immunopathology. NIAID’s approach integrates the basic science disciplines with relevant clinical specialties. Basic Immunology. The biology and chemistry of the immune system and its products are the concerns of this program area. Immunobiologic studies focus on the origin, maturation, and interactions of the immune system's major cells, lymphokines, and other substances produced by theses and other cells that mediate immune reactions. Studies include mechanisms responsible for induction and regulation of the immune response. Immunochemical research encompasses the delineation of the chemical structure and function of antigens and antibodies; chemical basis of immunologic specificity; regulation of immunoglobulin synthesis; and mechanisms of antigen-antibody reaction. Research projects are designed to: Elucidate the critical immunologic functions of T cell receptors, cell-adhesion molecules, and cytokines and their receptors in various systems in the human body and in laboratory animals; Isolate and characterize human stem cells; Participate in the formulation of a repository of cell lines and gene probes for use in the study of mucosal immunity and digestive diseases; Elucidate the chemical nature and structure of small organic molecules that generate allergic and hypersensitive responses; and Investigate the interactions of selected immunotoxicants with the secretory immune subsystems of the gut and respiratory tract. ; Genetics and Transplantation. Primary goals of genetics and transplantation research are to: Clarify the organization and mechanisms of expression of the genes on which immune function depends; Characterize protein products of genes, including histocompatibility antigens; Determine how these gene products condition the response to foreign antigens; and Develop regimens to modulate the immune response and facilitate engraftment of transplanted organs and tissues. By supporting the acquisition, characterization and distribution of tissue typing reagents and the evaluation and improvement of tissue typing methodologies, the program facilitates the matching of donors and recipients for transplants. It also supports studies on the relationship of the human major histocompatibility complex (MHC) HLA antigens to disease susceptibility. Research projects in this area are designed to: Investigate the mechanisms and innovative use of immunosuppressive drugs; Develop new monoclonal antibodies directed against specific cells to prevent graft rejection; Further develop reagents for precise typing of MHC or tissue matching; and Delineate the development of the fetal and adult immune response, using in vitro systems.   Identification and Acquisition of Reagents. NIAID contracts serve as sources of standard reagents to identify cell surface antigens both within and outside of the major histocompatibility complex that play a role in immune response. Some of these reagents are available for use in workshops or similar large-scale studies. The institute also is a primary source of standard reagents for distribution and analyses for basic immunogenetic studies of murine transplantation antigens.   Transplantation. Program projects in transplantation immunology, located at major transplant centers, are funded by NIAID to facilitate rapid translation of basic immunologic discoveries into clinical use. The centers carry out basic and clinical research pertinent to mechanisms of rejection, organ availability and preservation, and management of rejection. National Cooperative Clinical Trial in Transplantation. NIAID established this trial to expedite the evaluation of new treatment modalities to prevent kidney graft rejection. Multicenter clinical trials to assess the potential efficacy of various therapies are conducted at eight kidney transplant units throughout the U.S. Asthma, Allergy and Inflammation. More than 50 million Americans suffer from allergic diseases including asthma. NIAID supports studies encompassing the cause, pathogenesis, diagnosis, prevention, and treatment of allergic diseases. Various types of allergic problems under investigation include: immediate type hypersensitivity and its disorders, including asthma, allergic rhinitis, atopic dermatitis, urticaria and angioedema; allergic reactions and disorders caused by insect bites and stings, foods, airborne allergens, and infectious agents; manifestations of delayed hypersensitivity and contact dermatitis; and mechanisms of drug reactions and chemical sensitization. Studies also include structure of antibodies, particularly IgE, and chemical mediators released by interaction of antigen and antibody with target cells; isolation and chemical characterization of the active fractions of allergenic agents; and therapy and prevention of allergic disorders and hypersensitivity reactions by immunotherapy with specific antigens or drugs. Asthma, Allergic and Immunologic Disease Cooperative Research Centers. A network of cooperative research centers represents an effort to integrate the basic concepts of immunology, genetics, biochemistry, and pharmacology into clinical investigations of patients with asthma, allergic and immunologic diseases. The program encourages collaboration between basic and clinical scientists, provides a research environment for such interactions, and implements clinical application of adequately tested research findings and procedures. It is believed that this will lead to an understanding of the pathophysiologic, biochemical, and immunologic mechanisms of these disorders. National Cooperative Inner-City Asthma Study. NIAID established this study to assess factors contributing to the increased morbidity and mortality from asthma among children residing in urban areas, and to develop and evaluate a comprehensive therapeutic, educational, and environmental intervention program designed around those contributing factors. Seven sites in six cities nationwide are participating in this cooperative study. Clinical Immunology. Investigations of underlying mechanisms of disease and applications of basic knowledge to the cause, prevention, and management of immunologic disorders are approached from either of two disciplines--clinical immunology or immunopathology. Studies of clinical immunology involve acquired and inherited diseases associated with dysfunctions of the immune system, whereas immunopathology studies encompass genetics, cytology, biochemistry, pathology, and pharmacology of the immune system. Areas under investigation include: Immune deficiency diseases arising from primary defects in development or maturation of the immune responses; acquired immune deficiency disorders excluding AIDS; clinical manifestations mediated by products of lymphocytes; diseases associated with immune complexes and autoimmune phenomena; and immunotherapy of disease process, including the use of immunopotentiating and immunoregulatory substances. DAIT supports program projects in mechanisms of immunologic diseases and autoimmunity aimed at increasing the understanding of pathophysiologic processes of immune-mediated diseases and the development of improved methods of diagnosis, treatment and prevention of immune system disorders. b> Division of AIDS The Division of AIDS (DAIDS) was formed in 1986 to address national research needs created by the advent and spread of the HIV/AIDS epidemic. DAIDS is ensuring that federally supported scientific investigation of HIV infection is focused and appropriately balanced on the most critical biomedical research issues. Specifically, the mission of DAIDS is to increase basic knowledge of the pathogenesis, natural history, and transmission of HIV disease and to promote progress in its detection, treatment, and prevention. DAIDS accomplishes this through planning, implementing, and evaluating programs in: 1) fundamental basic and clinical research; 2) discovery and development of therapies for HIV infection and its complications; 3) discovery and development of vaccines and other preventive interventions; and 4) training of researchers in these activities. An extramural portfolio of grants and contracts addresses research in these areas. HIV Pathogenesis. Research on the pathogenesis of HIV infection will advance understanding of the biological causes of HIV-related disease and serve as a foundation for advancing treatment and prevention. Investigator-initiated research and the traditional research grant are the foundation of division activity in this area. Important research gaps are identified by division staff in concert with investigators and advisory committees. Other key NIAID resources for the study of pathogenesis include: longitudinal epidemiological studies of cohorts of individuals infected with, or at risk of infection with, HIV, and serially collected specimens stored in an DAIDS-supported repository; animal model research and development projects; the NIAID AIDS Reference and Reagent Repository, through which DAIDS acquires and distributes essential research reagents to scientists around the world; and the Centers for AIDS Research (CFARS), designed to support coordinated scientific and administrative activities that enhance the capacity for collaboration between basic and clinical research.   Epidemiology and Natural History. The division’s goals in epidemiology and natural history are to foster population-based research that will advance understanding of the biology and clinical course of HIV infection and serve as a foundation for advancing treatment and prevention. The division oversees several large longitudinal cohort studies that conduct multidisciplinary research involving specific populations of individuals infected with or at significant risk of infection with HIV. These include: Multicenter AIDS Cohort Study, San Francisco Men’s Health Study, and Women’s Inter-Agency HIV Study. In addition to collecting clinical data obtained at serial examinations and interviews, all of these studies are linked to a DAIDS-supported repository that stores a variety of serially collected biological specimens from participants and subsequently retrieves them for use in experiments conducted by investigators around the world. These studies therefore represent a powerful investigative tool for basic and applied research in pathogenesis, diagnosis, behavior, treatment, and prevention. Vaccine and Prevention Research and Development. Development and testing of vaccines and other biomedical interventions such as drugs and microbicides to prevent HIV disease is a key role of DAIDS-funded research. NIAID supports vaccine research from early concepts through clinical trials. This comprehensive approach to vaccine development includes fundamental and vaccine evaluation research. Institute efforts in vaccine research and development are built on a strong foundation of investigator-initiated research in basic virology, immunology, and microbiology. In addition, DAIDS uses a number of specific resources to stimulate development of new vaccine concepts and to ensure that this infrastructure emphasizes a rational, deliberate process for moving concepts through to clinical trials. The Innovation Grant Program for Approaches in HIV Vaccine Research encourages novel and innovative concepts in vaccine discovery and development. Little preliminary date are required. Fifty-eight grants are currently funded in the following research areas: 1) structure and function of the HIV envelope protein (Env), 2) improved animal models for vaccine and pathogenesis studies, and 3) mechanisms of directing antigen processing in vivo to maximize the immune response. Some exciting research include: twinning and cloning of monkeys, transgenic small animal models, strategies to target HIV T cell epitopes, and new vectors. The HIV Vaccine Research and Design Program (HIVRAD) supports concepts that have evolved beyond early testing and "matured" innovation grants. Other general vaccine research that does not involve a clinical component, such as animal model development and work on correlates of immunity, is also supported by HIVRAD. The Integrated Preclinical/Clinical Program funds the iterative processes of product development, optimization, and refinement. Through this program, consortia vaccine and development teams conduct research on promising vaccine concepts that are amenable to product development and are likely to lead to preliminary studies in humans. Other areas include: the AIDS Vaccine Evaluation Group (AVEG), which conducts phase I and II clinical trials of candidate HIV vaccines; central immunology laboratory facilities in support of activities of NCVDGs, SIV-VEUs, the chimpanzee unit, and the AVEG; HIV Variation Project, which investigates the rate and magnitude of genetic variation in HIV and related retroviruses and explores the impact of this variation on strategies to develop HIV vaccines; Cooperative Group for Investigations of AIDS Vaccine Adjuvants, which supports investigator-initiated research into mechanisms of adjuvant action, develops new adjuvant formulations to stimulate immune responses and generate long-lasting immunity and immunological memory, and evaluates vaccine-adjuvant combinations in relevant animal models; and HIV Network for Prevention Trials (HIVNET), which consists of both domestic and international sites that conduct trials of HIV vaccines and other prevention strategies. Researchers at HIVNET sites also study cohorts of individuals at high risk for HIV infection to prepare for conducting vaccine efficacy trials within these populations. Therapeutics Research and Development. The division’s goal in therapeutics is to foster the discovery and development of interventions that will improve the quality and duration of life of HIV-infected individuals. NIAID devotes substantial resources to the discovery stage of therapeutics research, attempting to focus resources on areas of promise that are receiving insufficient attention from the private sector. The effort begins with a strong commitment to basic research in microbiology and pathogenesis. Upon this are built programs of targeted drug discovery with the National Cooperative Drug Discovery Groups (NCDDGs) for HIV and opportunistic infections (OIs) at the center. These consortia of academia, industry, and government investigators work collaboratively on focused "gap" areas of targeted drug discovery. Small portfolios of highly applied traditional investigator-initiated research round out this effort. NIAID’s preclinical development resources are limited in scope to those necessary to ensure that the national effort has the capability to carry out specific rate-limiting developmental steps involving selected highly promising candidate agents that lack a private sponsor with sufficient resources or commitment. These "gap-filling" resources include capabilities for 1) chemical resynthesis; 2) analytical chemistry and quality control; 3) dosage form development and manufacturing; 4) small and large animal toxicology; and 5) in vitro screening and animal model efficacy studies. In addition, the Strategic Program for Innovative Research on AIDS Treatment (SPIRAT) fosters coordinated and interdependent basic and clinical research between current HIV pathobiology and clinical evaluation of novel therapeutic strategies. NIAID conducts clinical trials of new therapeutics in adults in two networks: Adult AIDS Clinical Trials Group--a large, multicenter clinical trials network; and Terry Beirn Community Programs for Clinical Research on AIDS--designed to address questions of importance to primary care clinicians and extend opportunity for participation in trials to persons underrepresented in HIV research. The Pediatric AIDS Clinical Trials Group supports resources specifically for children and adolescents Division of Intramural Research The institute’s Division of Intramural Research (DIR) consists of 16 laboratories, of which 13 are on the Bethesda campus and at off-campus sites in Frederick and Rockville, Md., and 3 are located at the Rocky Mountain Laboratories in Hamilton, Mont. Scientists in these laboratories conduct basic and applied research in immunologic, allergic, and infectious diseases and related clinical disorders. Considerable effort is devoted toward vaccine development and the understanding of the immune system’s ability to react to certain antigens. The scope of laboratory investigations includes the disciplines of virology, parasitology, mycology, microbiology, biochemistry, immunology, immunopathology and immunogenetics. Additionally, DIR supports a 52-bed inpatient service and an outpatient facility located in the Clinical Center on the NIH campus. Patients with a variety of diseases under study, including AIDS, vasculitis, immunodeficiencies, host defense defects, unusual fungal infections, asthma, allergies, various parasitic diseases and disorders of inflammation, are seen. Frequently patients participate in new and exciting treatment or diagnostic procedures derived from ongoing laboratory research efforts. Successful vaccines or therapies for infectious diseases derive from a myriad of research activities on the disease agent as well as interactions of the agent with the host. HIV associated with AIDS is a major challenge to DIR scientists and physicians. The creation of suitable laboratory animal models is critical to developing therapeutic strategies and vaccines for AIDS. DIR scientists study the immunopatho-genesis of HIV infection as well as immune response to the virus. Cytokines have been shown to induce the expression of HIV in latently or chronically infected cell lines, thus providing tools for understanding mechanisms of the insidious progression of immunosuppression in HIV-infected individuals. In addition, NIAID researchers explore the many components of HIV disease, including phases of immune system activation and suppression. In studying dissemination of HIV to lymphoid tissues in the body such as the lymph nodes and spleen, investigators have found that HIV is active within these tissues from the earliest stages of HIV infection. This finding provides a scientific rationale for early treatment when safer and more effective antiretroviral drugs become available. DIR investigators have conducted intensive studies of antiretroviral and immunomodulator therapies. Clinical trials of a number of therapies, including use of IL-2 to maintain CD4 levels, are under way. NIAID intramural scientists are working to develop and test vaccines against a number of infectious agents such as viruses causing AIDS, dengue fever, diarrhea in infants, and pneumonia and croup in infants and young children. Bacterial agents that cause sexually transmitted diseases such as chlamydia and gonorrhea, and Lyme disease are under active investigation. Approaches to the development of a vaccine against malaria are being explored. Promising new vaccine candidates are tested in the clinical setting for safety, immunogenicity, and if warranted, efficacy. Basic immunologic studies are aimed at defining components and mechanisms of action of humoral and cellular responses. Receptors on T lymphocytes and peptides linked to the surface of antigen-presenting cells are being defined. Information derived from these studies may allow design of peptides that can inhibit specific immune responses and may have great importance in controlling rejection associated with transplantation. DIR researchers carry out intensive studies of the role of newly discovered cytokines in T-cell differentiation. Researchers have found that interleukin 12 (IL-12) plays a pivotal role in induction of T-cell responses, which are important for control of intracellular infections. B lymphocytes, critical components of the immune response and responsible for antibody responses, are being dissected for studies of structure and function. Among studies being conducted are those related to control of B-cell immunoglobulin class switching. It has been shown, for instance, that IL-4 and INF-gamma reciprocally regulate IgG1 and IgE responses in mouse systems. In addition, the role of TGF-beta in IgA class-switching has been clarified. These studies are important in the design of future vaccines that can enhance production of certain forms of antibody. Inflammation is an important aspect of immunity. One important mediator of inflammation is a series of nine proteins called the complement system. NIAID scientists identified a new protein present in large concentrations in plasma of humans. The new protein binds to the fourth protein of the complement cascade where it acts as an inhibitor of this important inflammation-producing system. The inhibitor also interacts with kinin-generating and coagulation systems. Certain patients with unusual swelling disorders have an abnormality in the degradation of this protein, and thus the protein may be very important in certain swelling disorders. The first evidence that immunodeficiency can be treated with a naturally occurring product of lymphocytes was recently demonstrated by DIR scientists. Chronic granulomatous disease of childhood (CGD), a disease in which there is a defect in the ability of scavenger cells of the immune system to produce hydrogen peroxide, renders the patient susceptible to certain infectious agents. A multicenter clinical trial of interferon gamma in patients with CGD followed in vitro studies which demonstrated the effectiveness of interferon gamma in correcting the defect in phagocytes from these patients. Interferon gamma was shown to significantly reduce the number of serious infections in CGD patients. These studies led to FDA approval of this drug for use in CGD. Studies of immune response to the causative agent of leishmaniasis have demonstrated that immunity to the parasite is not only to a specific antigen, but also to a certain immune cell. DIR scientists have shown that outcome of leishmaniasis depends on whether the animal develops a TH1 response with T cells that produce IL-2 and IFN-gamma, or a TH2 response with T cells that produce IL-4 and IL-5. In the former case, granulomas develop that wall off and kill leishmania in the latter, the infection is disseminated. Studies of allergy are carried out by investigators working in basic immunology laboratories as well as by clinical and laboratory investigators working within the Asthma and Allergic Diseases Center. One effort has been the study of IgE antibody which mediates allergic responses by causing mast cells to release mediators of allergic responses. IL-4, produced by T cells, is essential for production of IgE in mice. Administration of IL-4 to mice prevented increases in IgE antibodies normally observed in immune responses to certain antigens. In other studies, DIR scientists have developed a "knockout" mouse that lacks receptors for IgE antibodies on the surface of mast cells. These mice will facilitate a better understanding of the role of IgE responses in the production of allergic symptoms. Studies of the mechanisms of allergies have emphasized work on mast cells. Mast cells are the central cells of allergic responses because when activated by an allergen and IgE they release the mediators of allergy. New techniques have been developed in order to grow human mast cells in culture, an advancement that will enable more detailed investigations into their biology. An improved approach to the treatment of asthma has been devised by DIR researchers. The concept is based upon separating bronchodilators from agents that act to reverse specific processes in the pathogenesis of asthma. Specifically, patients are placed on symptomatic therapy in order to permit the more specific therapy to act. Inhaled cromolyn, systemic corticosteroids and immunotherapy are employed as specific agents while beta adrenergic agonists, theophylline, and atropine are symptomatic agents. This approach is gaining increased acceptance and should improve long-term treatment of asthma.

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