Introduction

Because of the unique nature of HIV--the way the virus enters a cell, causes infection, affects every organ system, and unleashes a myriad of opportunistic infections and cancers--and the pace at which the knowledge base has been expanded, AIDS research also is unraveling the mysteries surrounding many other infectious, malignant, neurologic, autoimmune, and metabolic diseases. In addition to its direct and indirect medical applications, basic knowledge of the biology of HIV infection and the processes by which it causes AIDS benefits other areas of basic research including immunology, virology, microbiology, molecular biology, and genetics. The study of drugs to treat HIV infection and its complications also has helped to establish new approaches for the design and conduct of more rapid clinical studies, as well as those that address the special recruitment requirements of women, minorities, and other underserved populations. In addition to learning more about the special recruitment requirements of these populations, the investment in behavioral and social sciences research has provided effective strategies for intervening in other diseases modified by individual behavior.

The investment in AIDS research has provided a new paradigm for confronting viral diseases in general. Prior to the development of new potent antiviral drugs, virtually all efforts to combat viral diseases involved prevention (using vaccines) or palliation (treating symptoms). Few effective treatments were available for most common viral infections. The AIDS drug development experience has not only benefitted development of treatments for other viral diseases, but also will hasten drug development efforts for bacterial, mycobacterial and fungal diseases.

• The successful development of four classes of drugs that limit the replication of HIV, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and nucleotide analogs, represents a landmark in drug development for the control of viral diseases. The first drug in a new class, fusion inhibitors, was just approved by the Food and Drug Administration (FDA).
  
  
• The identification of several new viral and host/cellular targets will permit the development of new drugs for HIV and other viral infections such as integrase inhibitors, assembly inhibitors, and zinc finger inhibitors.
  
  
•  The successful development of powerful multi-drug combinations capable of inhibiting viral replication in different stages of the virus life cycle represents an important approach to potentially controlling other viral infections and delaying disease progression.
  
  
• Experience gained from characterizing the HIV protease enzyme and developing protease inhibitors also is being applied to the design and development of potential agents against the coronavirus, which has been identified as the causative agent of severe acute respiratory syndrome (SARS). An antiviral agent against this virus may inhibit viral replication, halt disease progression, and prevent the high mortality rates associated with this disease.
  
  
• The drug lamivudine, (also known as 3TC, an inhibitor of the HIV reverse transcriptase enzyme), initially developed to treat HIV infection, has been shown to be effective for the treatment of chronic hepatitis B infection, and it has been recently approved by the FDA for this purpose. Prior to the availability of lamivudine, HBV could only be treated with injections of alpha-interferon, and many HBV-infected persons proceeded inexorably to cirrhosis, liver failure and liver cancer. Lamivudine is more effective than alpha-interferon in producing HBV disease remission and provides the important new option of an oral drug for the treatment of a disease that affects 300 million people world-wide. In addition, lamivudine represents a "lead compound" that should expedite the development of even more effective therapies to treat, and perhaps even cure, chronic hepatitis B infections.
  
  
• Another antiviral agent, adefovir divipoxil, (Hepsera), which failed as an HIV treatment due to kidney damage, was found in a much lower dosage to suppress HBV without damaging the kidneys, and was recently approved for treatment of chronic HBV disease.
  
  
• Development of combination therapy for HIV infection stimulated interest in utilizing combination therapy to treat hepatitis C infection. Pegylated interferon, initially tested on HIV-infected patients with Kaposi’s sarcoma, later was shown to be effective for the treatment of HCV infection.
  
  
• Experience gained from the development of protease inhibitors also is being applied to vaccinia virus (smallpox) research. There is currently no antiviral drug to fight smallpox. An antiviral drug might act as protease inhibitors do in HIV-infected individuals, preventing viral replication.
  
  
• Current therapies for cytomegalovirus (CMV) are toxic and expensive. Using techniques developed to derive inhibitors of the HIV protease, new candidate drugs have been designed that represent promising leads as agents to treat CMV infection.
  
  
• Using techniques successfully validated in the course of HIV drug development, progress has been made in targeting a number of steps in the influenza virus life cycle for inhibition.
  
  
• New animal models of viral diseases that have been developed by AIDS researchers will facilitate studies of other infectious agents and the diseases that they cause.

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AIDS therapeutics research, particularly the development of protease inhibitors, has convincingly demonstrated the importance of structural analysis in rational drug design and has resulted in a new generation of powerful inhibitors of HIV replication. Progress in this area depends on the identification of a promising molecular target for drug therapy, determination of the three-dimensional structure of the target molecular using sophisticated X-ray crystallographic methods, and structure-based drug design aided by the techniques of structural biology, optimization of ligand affinity and selectivity, and computer-based molecular modeling. HIV research has benefitted from the availability of these individual methods and, concurrently, has fostered significant improvements in each of these critical technologies, including X-ray crystallographic methodologies, nuclear magnetic resonance techniques, and computational approaches to medicinal chemistry. The continued support of these technological advances will benefit efforts to develop new drugs for other diseases. A number of the most promising anti-cancer drug candidates currently in clinical trials, including the mechanistically novel inhibitors of matrix metalloproteases, have been developed with a similar iterative structure-based approach to drug discovery. Structure-based drug design may also lead to the discovery and development of lead compounds against the coronavirus associated with SARS

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Individuals who receive drugs that intentionally or unintentionally suppress the function of the immune system are, like HIV-infected patients, at significantly increased risk of infection with microorganisms that generally do not pose a hazard to those with fully functioning immune systems. Many forms of treatment for cancer involve the use of drugs that suppress the immune system. Transplantation of solid organs to treat organ failure (e.g., heart, liver, or kidney) and bone marrow transplants to treat malignant (e.g., leukemia) or hematologic diseases (e.g., immunodeficiency syndromes or genetic disorders of hemoglobin production such as sickle cell anemia) necessarily involves the use of drugs that suppress the immune system to prevent rejection of the transplanted organs or tissues. The development of effective drugs to prevent and treat many of the microorganisms that cause such opportunistic infections (OIs) promises real benefit to those undergoing cancer chemotherapy or receiving anti-transplant rejection therapy.

• Clinical research to delay or prevent life-threatening AIDS-related opportunistic diseases has helped to stimulate the development of effective drugs to treat these pathogens in immunosuppressed persons, such as Pneumocystis carinii, cytomegalovirus (a cause of blindness in people with AIDS and life-threatening pneumonias and serious gastrointestinal infections in bone marrow and organ transplant recipients), and a variety of serious fungal infections that cause meningitis or disseminated infections.
  
  
• Research on AIDS therapies has helped establish the concept of "prophylaxis" of certain infections in immunosuppressed persons. Providing regular, low doses of drugs that are intended to prevent development of disease decreases the risk of opportunistic infection. This approach recently has been shown to be highly cost-effective in the course of treatment of HIV infection. Prophylaxis of OIs is now standard practice to prevent infections caused by a variety of bacteria, viruses (such as CMV), and fungi in immunosuppressed patients. However, it should be noted that the overall incidence of OIs has declined with the use of antiretroviral therapy (ART), and ART is now considered the most effective approach to preventing OIs.

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One of the cardinal manifestations of AIDS is the predisposition to develop specific types of cancer, including Kaposi's sarcoma and non-Hodgkin's lymphomas. That these cancers arise in the setting of host immunodeficiency provides strong support for the notion that the immune system can play an important role in suppressing the development of cancers. Because HIV suppresses the immune system and most AIDS-related malignancies are strongly associated with viruses, HIV infection provides a unique model to study the interplay of viruses, the impaired immune system, and the development of cancers. The HIV model also provides a unique opportunity to test novel approaches by which immune responses can be modified to help treat established malignancies.

• AIDS research has helped to broaden the understanding of the types of viruses potentially involved in the development of cancers. The discovery of the likely cause of Kaposi's sarcoma, the herpes virus known as HHV8, provides a model for using novel techniques of molecular biology to search for infectious cancer-causing agents in any type of cancer. Studies involving HIV-infected persons are now serving as the model to identify potential infectious etiologies for several common malignancies.
  
  
• IV-infected women who also are infected with human papilloma virus (HPV) are at increased risk of developing cervical cancer, suggesting that the immune system also plays an important role in controlling HPV disease. A link between HPV infection and cervical cancer also is seen in women not infected with HIV. Studies of HIV-associated cervical cancer have stimulated new areas of research and therapeutic strategies to treat this disease, which will likely benefit all women at risk of cervical cancer.
  
  
• Wasting, the intractable loss of weight, is a common clinical manifestation of both cancer and advanced HIV disease. New therapeutic approaches developed to treat HIV-associated wasting, such as recombinant human growth hormone, nutritional interventions, exercise, testosterone replacement, or anabolic steroids may prove to be of benefit to persons with cancer cachexia.
  
  
• The field of HIV-associated wasting syndrome research is rapidly changing as a result of the introduction of antiretroviral therapies (ART). New-onset diabetes, a series of metabolic abnormalities, and abnormal fat distribution have been described in HIV-infected individuals taking ART. Peripheral insulin resistance (the failure of target tissues to respond to normal levels of circulating insulin) is a major component of type 2 diabetes and obesity, and more recently has been implicated in the pathogenesis of the metabolic abnormalities associated with ART. Studies elucidating the pathogenesis of the metabolic abnormalities associated with HIV disease and ART may provide crucial insights into the underlying mechanisms of insulin resistance and may prove to be important in understanding the pathogenic processes operating in type 2 diabetes and obesity. Moreover, type 2 diabetes, central obesity, and metabolic abnormalities associated with ART are characterized by alterations in lipid profiles that may confer increased risk for cardiovascular disease. Elucidation of the mechanisms underlying these changes could be very important for designing interventions aimed at preventing cardiovascular disease in patients with type 2 diabetes.
  
  
• Research on anti-HIV drug resistance is providing important information for the design of more effective regimens with minimal drug resistance. Insight gained from these studies may be useful in better understanding the basic mechanisms involved in the development of single- and multiple-drug resistance and ultimately lead to the development of better treatment regimens for other infectious diseases.

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AIDS research has provided new paradigms for the diagnosis of infectious diseases and for monitoring the efficacy of therapy. Molecular diagnostic methods use sensitive techniques to detect and quantify the pathogen in an infected individual. These methods now permit more rapid diagnosis of infectious diseases, facilitate earlier introduction of effective therapies, permit the design of faster, more informative clinical trials, and allow the individualization of optimal therapies.

• Among these new technologies is the polymerase chain reaction (PCR) test used to diagnose HIV infection or the viral load assays used to assess disease progression and efficacy of anti-HIV therapies. The development of these approaches and their validation in the course of AIDS studies have helped speed the process of clinically testing candidate AIDS therapies, and similar approaches are now being employed to study treatments for other infectious diseases. PCR-based tests are now routinely used to rapidly diagnose a number of important infectious diseases including hepatitis C, tuberculosis, chlamydia, Lyme disease, and a variety of fungal infections. In hepatitis C treatment, just as in the management of HIV infection, PCR technology has proven to be useful in monitoring the impact of therapy.
  
  
• The application of these technologies to other diseases potentially caused by infectious agents, such as chlamydia linked to cardiovascular disease, has made it possible to screen large sample sets in a very short period of time to identify potential causative agents of poorly defined chronic illnesses.
  
  
• The development of tests to screen blood donations for the presence of HIV infection has stimulated advances in technologies that are currently being used to screen the blood supply for the presence of other important infectious diseases, such as hepatitis C virus, hepatitis B virus, and HTLV-1 and 2 viruses that are associated with the development of leukemia and serious neurologic diseases. As a result, the safety of the blood supply has been substantially improved.
  
  
• Rapid assays developed for the detection of HIV infection enable more HIV-infected individuals to learn their HIV serostatus, allowing them to take measures to prevent the further spread of the virus, as well as to seek medical care for treatment of their HIV disease. These assays are being developed for detection of HBV and HCV and may result in improved protection of the global blood supply.
  
  
• NIH-funded studies also are developing and testing innovative approaches for inactivating HIV and other blood-borne viral and bacterial pathogens such as hepatitis B virus and hepatitis C virus to ensure that blood and blood components are safe and do not result in transmission of diseases.

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The investment in AIDS research has enormously speeded the development of our understanding of the human immune system. Research on AIDS has led to major advances in our understanding of and ability to manipulate human immune responses. This research may allow more effective approaches to treat diseases in which dysregulated immune responses are either the actual cause of, or substantial contributing factor to, the fundamental disease process, including allergies, multiple sclerosis, juvenile diabetes, heart disease, rheumatoid arthritis, and systemic lupus erythematosus.

• Promising immunologic approaches currently being investigated to control cancer include the use of cytokine therapy to boost anti-tumor immune responses, the use of genetically modified tumor cells that express cytokines or other gene products intended to re-direct host immune responses to more effectively fight the resident tumor cell burden is another by-product of HIV research on the human immune system. The expansion (in tissue culture) and transfer of immune cells that can recognize and kill tumor cells (activated T cells or cytotoxic T cells) has already been tested in the treatment of certain solid tumors, in conjunction with chemotherapeutic agents. Similar approaches have been actively pursued in the course of research on HIV therapies, and experience from studies in HIV-infected individuals has helped accelerate the development and testing of these treatments in the context of cancer therapy.
  
  
• New approaches developed for AIDS research have demonstrated specific genetic variations affecting immune system cells that protect against atherosclerosis. Establishing a link between a specific cell receptor and heart disease will permit the development of drugs targeted to this receptor in order to block its action.
  
  
• New technologies developed through AIDS research to measure the in vivo functioning of the immune system are radically changing the field of immunology. These include: a non-radioactive endogenous labeling technique to directly measure the kinetics of circulating T lymphocytes in normal and disease states; a technique to assess changes in thymic function with age and during illness; and a methodology to assess the number and distribution of antigen specific cytotoxic T cells, which are among the most important players in clearing viral and other pathogen infections. The availability of these techniques is affording medical researchers the opportunity to effectively measure immune function in both healthy and infected individuals. These findings have far-reaching and important implications for our understanding of the pathogenesis of immune diseases and the development of effective vaccines against infections.
  
  
• New methodologies developed in the context of AIDS research are radically changing our thinking about the function of the thymus throughout the lifetime. The deletion circles technology that enables the identification of T cells recently emigrated from the thymus was instrumental in demonstrating that the thymus remains active late in life and contributes a diverse set of functional T cells to the peripheral circulation. This knowledge is of fundamental importance in understanding the biology of the human thymus, the role of the thymus in reconstitution of the immune system in adults, and the role the thymus plays in post-natal production of auto-reactive T cells in autoimmune diseases.

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NIH-sponsored AIDS research programs have brought about unprecedented cooperation among federal, university, and pharmaceutical industry scientists in the design, development, and testing of potential therapeutic agents and vaccines. AIDS research has resulted in new approaches in the design and conduct of clinical trials, as well as in recruiting and enrolling patients, especially women, children, IDUs, and minorities in these studies. These models are now being applied to test treatments for other diseases in faster, more efficient, and more inclusive protocols.

• New approaches for conducting clinical trials have been developed, including community-based trials, which capture the expertise of community physicians. NIH-sponsored AIDS clinical trials have demonstrated the importance of providing ancillary services, such as general health care, transportation, obstetrical care, day care for children, and other related services, to recruit and ensure the continued participation of women, children, adolescents, and minorities in clinical trials.
  
  
• AIDS clinical studies pioneered the development of community advisory boards to assist clinical trial sites in ensuring close cooperation with community constituency groups. These strategies are now being applied in the study of treatments for other diseases.
  
  
• The "parallel-track" mechanism has been shown to be consistent with the conduct of effective clinical studies of candidate therapies and will benefit persons suffering from all types of life-threatening diseases for which existing therapies are either ineffective or have failed. This mechanism permits access to promising drug treatments, prior to their formal approval by the FDA, for individuals who would not otherwise qualify for participation in specific clinical studies.
  

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Research aimed at understanding how HIV enters the central nervous system (CNS) and how it results in neurologic disease has yielded important knowledge regarding the role that severe inflammatory processes within the CNS can have in neuronal degeneration and impairment of cognitive and motor functions. AIDS research has provided direct insights into the mechanisms by which neurotoxic molecules released by inflammatory processes in the brain induce neuronal injury and death.

• The recent discovery of chemokine receptors has opened new avenues of research that will probably lead to a better understanding of the nervous system in both normal and disease states. Research on chemokines and chemokine receptors has already stimulated investigations into trafficking of immune cells into the brain, provided in situ examples of blood/brain barrier (BBB) permeability, challenged old concepts of the brain as an immune-privileged site, and provided suggestive evidence of a possible role for chemokine receptors in the developmental formation of neural circuits in the hippocampus.
  
  
• Studies on the mechanisms involved when HIV crosses the BBB to infect cells within the brain and how drug therapies can be delivered to the brain and CNS have led to a better understanding of the mechanisms through which this barrier functions and how it may be circumvented.
  
  
• Neuro-AIDS has become a fertile area of investigation for multiple neurologic diseases since it reflects numerous ways in which the nervous system can be susceptible to infection, to inflammatory processes, and to ways in which viruses can remain latent for years. As such, the results of these studies have important implications for research on Alzheimer's disease, dementia, multiple sclerosis, neuropsychological disorders, encephalitis, and meningitis.

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The investment in AIDS research has enormously facilitated our progress in many areas of basic science. Indeed, this effort has been a major contributor to the knowledge base upon which the biotechnology industry has been built. Biotechnology companies are capitalizing on new basic biomedical information provided by AIDS research, most notably new findings regarding chemokines and novel proteins as targets for drug and vaccine development. The discovery of a series of chemokine receptors necessary for HIV entry into a cell has opened new research opportunities for studies on virus/host interactions and research on receptor biology. Findings from these studies may lead to novel therapeutics that can block cell surface receptors, thus potentially preventing further spread of viral infections and disease progression.

• AIDS researchers have reported using a large protein molecule to kill HIV-infected cells. A similar mechanism may also be useful in destroying cancer cells and cells infected with hepatitis C virus, herpes virus, and other infectious agents.
  
  
• Basic research on HIV has elucidated the mechanism the virus uses to infect target cells. This mechanism, which includes the virus injecting its genetic material into another cell, may potentially be used to deliver gene therapy for hemophilia and other genetic diseases.

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Support of basic cancer research in the 1960s and 1970s provided several key tools and techniques for identifying subsets of human lymphocytes and retro/lentiviruses that made it possible to identify HIV and to elucidate the AIDS disease syndrome. Seminal research in basic immunology that identified mouse T-lymphocyte subsets led to parallel studies in human blood and lymphoid tissue. By 1980, the reagents that were needed for characterizing human T cells permitted the rapid characterization of severe lymphocyte loss in immunodeficiencies and the rapid comparison of the acquired immunodeficiency syndrome that initially appeared to be affecting gay men, infants, and blood transfusion recipients. In turn, clinical research in HIV-infected patients has generated a large knowledge base on lymphocyte subsets and immune activation markers that is being applied to autoimmune diseases and infectious diseases of both children and adults.

• The need for sample assessment in AIDS clinical trials drove the improvements in technology to permit rapid, high quality, multiparameter assessments of blood cell subsets using small quantities of blood samples. These assessments are now being applied to a wide range of genetic and infectious diseases.
  
  
• The need to define and understand a correlate of immunity for HIV vaccine development has rapidly translated basic research from studies in mice to studies in HIV-infected individuals and HIV vaccinees. Studies on the specificity of T-cell responses in asymptomatic HIV-infected individuals have resulted in the development of new tools such as Major Histocompatability Complex (MHC) tetramers and T-cell receptor (TCR) spectrotypes and explored their application to understanding the efficacy of such responses to control virus replication in vivo. In the pressing need for a safe and efficacious AIDS vaccine, these novel technologies are being applied to understanding whether AIDS vaccine candidates are inducing specific T-cell responses. As a result of the unparalleled explosion of research in this area, there currently are more well-defined epitopes of HIV than any other infectious agent and the nature of immune responses to many viruses are being defined for application to other viral diseases. This has major impact on the development of vaccines for other viral diseases.
  
  
• The samples collected from cohorts of HIV-infected persons also have been used to explore the genetic factors (i.e., the distribution of mutant allelic forms of chemokine receptors in human populations) associated with infectious diseases. This research would not have been possible without the epidemiological and clinical studies to identify the causes, susceptibility, and progression of disease in HIV-infected individuals.
  
  
• The preclinical and clinical testing of new vaccine adjuvants in candidate HIV vaccines in uninfected HIV vaccine volunteers was a major step that demonstrated that there were limits to the direct application of data from vaccine testing in various species of rodents. Complementary basic research supported by AIDS funding has led to the molecular assessment of the differences in cytokine stimulation between rodent and primate species.

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Basic behavioral and social science research has yielded information about the interpersonal dynamics and social settings in which HIV-related and other risk behaviors occur and the impact of the HIV/AIDS epidemic on individuals, families, communities, and societies.

• Ethnographic studies of drug-using networks led to the revelation that HIV was being transmitted through the sharing of syringes, needles, cottons, cookers, and other drug paraphernalia and through identifiable webs of social and sexual relationships. In addition to its relevance for other chronic, infectious diseases endemic in the IDU population, including hepatitis and STDs, this information, and the qualitative and quantitative techniques used to obtain it, have contributed to our general understanding of disease transmission within defined social and geographic spaces.
  
  
• Scientifically rigorous national probability surveys among adults and adolescents conducted in the context of HIV/AIDS, have increased our knowledge of human sexual behavior, including the dynamics of partner selection, peer and family influence, and the role of drugs and alcohol in HIV risk behavior. These surveys also have provided the first accurate picture of the sexual behaviors in which people are actually engaging. This knowledge is important for projecting not only HIV transmission among different groups but also fertility and family planning trends.
  
  
• HIV-related interview and survey research has revealed that often a constellation of physiological, psychological, and social factors make certain people and groups more vulnerable than others to co-occurring diseases and conditions. The term "syndemics" has been coined to characterize the synergistic relationship of such co-occurring epidemics as HIV, hepatitis C, tuberculosis, drug use, mental illness, poverty, and childhood sexual abuse (in various combinations) that have been documented among groups of injecting drug users, women, and gay men. Better understanding of the nature of these syndemics and their contribution to risk of a number of diseases and disorders will lead to more effective public health interventions.
  
  
• HIV-related social and demographic research has revealed the nature and extent to which infectious diseases can have a devastating impact on family and household structure and function, community stability, and even national security. Demographers working in Sub-Saharan Africa and Thailand have documented the ways in which HIV and AIDS have forced the elderly to care for sick adult children and grandchildren (often orphaned) who otherwise would be providing for them in their old age. The implications of the demise of much of the working-age population in many communities is profound, affecting food security, productivity, and what meager social security systems already exist. The ability to monitor trends in HIV/AIDS-associated morbidity, mortality, and migration and their impact on such heavily affected societies contributes much to our understanding of the threat of other infectious diseases.

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• Behavioral and social interventions formulated from an expanded knowledge base have demonstrated efficacy in reducing HIV-related risk behaviors--e.g., increasing condom use, reducing the number of sex partners, delaying the onset of sexual intercourse, reducing frequency of needle sharing among IDUs, referring IDUs to drug treatment programs, etc.--and reducing HIV and STD incidence in a range of population groups and settings. The development and improvement of HIV-related behavioral intervention science has benefitted all areas of health promotion and disease prevention, including nutrition, smoking, alcohol and drug use, and pregnancy prevention.
  
  
• Psychosocial interventions aimed at reducing HIV-related sexual risk emphasize the development of behavioral skills, such as self-efficacy and the ability to negotiate with partners over condom use or sexual abstinence. These behavioral skills are important for other health and social life situations, including pregnancy prevention, avoidance of drug and alcohol abuse, and conflict resolution/violence prevention.
  
  
• Outreach interventions that employ peer leaders and social networks, such as those developed for out-of-treatment drug users to deliver HIV-prevention messages and services, are applicable to other health promotion and disease prevention efforts, such as nutrition and exercise campaigns.
  
  
• A key strategy for preventing the onset of HIV-associated opportunistic infections and further progression to AIDS is strict adherence to prescribed regimens of anti-HIV medications. Experts agree that the virulence of HIV infection demands nearly 100% adherence to anti-HIV treatments for them to be effective. Research on enhancing adherence among HIV-infected patients has produced a number of new psychosocial and technological methods that are applicable to other health arenas, especially those that involve taking a number of different medications on different schedules. Key among these are interventions that focus on the patient-provider relationship, which have been shown not only to improve adherence to medications but also communication and trust between parties in general.

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Addressing HIV transmission and prevention has required the development of better methods of measuring and assessing sensitive sexual and drug using behaviors within their social context.

• The development and refinement of computer assisted survey instruments (CASI), such as the audio version (ACASI), has allowed researchers to obtain information of a highly sensitive nature from individuals in a more private manner than an interview would allow. Self-reported information yielded from these technologies is believed to be more truthful than that obtained by other methods of inquiry. CASI and ACASI have been used extensively to obtain information about patterns of sexual behavior important to understanding the social dynamics of not only of HIV/AIDS but also STDs, substance abuse, fertility, family planning, and relationship formation.
  
  
• Qualitative and quantitative techniques for mapping social networks have been instrumental in charting the movement of HIV epidemics in different social groups and communities. These include ethnographic methods involving careful observation of behavior, and complex computer software that can provide multi-dimensional images of social networks. These techniques have important applications for social and behavioral epidemiology not only related to HIV/AIDS but also to other infectious and non-infectious diseases and to social and cultural movements related to health risk and protection.
  
  
• HIV/AIDS-associated social and bio-statistical modeling research has significantly improved our understanding of trends in the epidemic and their impact at a population level. New analytic and predictive tools have been developed that help calculate past histories and future trajectories of disease under different scenarios, including widespread implementation of interventions, such as a preventive vaccine or microbicide with a limited level of efficacy. Advances in cost-effectiveness analyses of HIV-preventive interventions are relevant to many other areas of public health.

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The emergence of HIV infection, SARS, Ebola virus infection, and hantavirus infection within the past 15 years has demonstrated not only that new diseases can appear in human populations but that they will likely continue to "emerge" in the future. Diseases once deemed "under control" also have re-emerged as important health problems in this country and around the world. Studies of the origin of HIV infection and the processes that contributed to its worldwide spread have significant implications for preventing or limiting similar epidemics in the future.

• HIV infection in humans appears to have originated from a virus present in certain non-human primates. Inadvertent transmission of the virus across species (so-called zoonotic infection) allowed the virus to enter human populations. Study of the origins and spread of HIV infection will provide a better understanding of how this process occurs and how it can be prevented.
  
  
• Experience gained from developing and testing vaccines against the multiple clades of HIV will be useful in the design of vaccine candidates against the numerous strains of the SARS coronavirus.
  
  
• Studies of HIV-infected individuals with clinical syndromes of previously unknown etiology have led to the discovery of a number of important new infectious agents including: human herpes virus 6 (HHV6), the cause of a number of clinical illnesses including exanthem subitum in children; human herpes virus 7 (HHV7), not yet associated with a specific clinical illness; human herpes virus 8 (HHV8 or KSHV), the likely causative agent of Kaposi's sarcoma; bacteria of the genus Rochalimaea, also known as Bartonella, the causative agent of bacillary angiomatosis and "cat scratch fever"; and a variety of previously uncharacterized fungi. The discovery of these agents and diagnostic methods to detect them also led to their identification in persons not infected with HIV. HHV6, for example, causes serious clinical complications in persons not infected with HIV and has recently been implicated in the development of multiple sclerosis.
  
  
• Using molecular diagnostic techniques developed in the study of the AIDS epidemic, CDC researchers were able to rapidly identify hantavirus as the causative virus infection of an outbreak of cases of fatal pneumonia in the Southwestern United States a few years ago. These techniques allowed the researchers to determine the origin of the virus in local populations of mice and to limit the further spread of infection among humans.
  
  
• The development of international collaborations for tracking the natural history and epidemiology of infectious diseases and for obtaining and identifying variants of infectious agents from different geographic regions helped expedite AIDS research. This experience, and the collaborations established, will be of significant value should new epidemic diseases emerge in the future.
  
  
• Computational methods and mathematical modeling developed to study HIV transmission now are being applied to track the parameters of transmission and dissemination of the bovine spongiform encephalopathy agent and will certainly benefit the study of other infectious agents as well.
  
  
• An improved understanding of the genes and mechanisms responsible for drug resistance will permit the development of new and more effective drugs and the control of potential epidemics of multi-drug resistant strains of HIV, Mycobacterium tuberculosis, and other microorganisms.

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