NIAID: Planning for the 21st CenturyDate: November 1, 1999
Source: National Institutes of Health (NIH)
Author: National Institute of Allergy and Infectious Diseases (NIAID)
Since HIV was first identified in 1983, enormous progress has been made in understanding how the virus attacks the immune system to cause disease and in how to intervene therapeutically. NIAID-supported scientists have led much of this progress. New techniques have enabled researchers to detect HIV in blood and tissue, and new therapies have achieved excellent results in suppressing the virus and delaying disease progression and death. NIAID-funded researchers have also made great strides in reducing mother-to-infant transmission of HIV. In the area of prevention research, 27 different vaccines have been evaluated, and efforts are under way to increase the number of new vaccine and microbicide candidates that can be tested.
Despite this progress, complex scientific obstacles and questions remain before AIDS can be effectively controlled. Research is needed to identify new strategies and tools to accelerate drug and vaccine discovery, to better understand immune reconstitution, and to determine the most promising drug candidates. Viral drug resistance remains a major obstacle to effective, long-term therapy, and new therapeutic regimens are necessary to minimize viral replication and burden in the body. Research on new therapies must also assess the metabolic complications and long-term effects of antiretroviral treatment. For vaccine development to move forward, questions about the significance of latently infected resting T cells, HIV and human leukocyte antigen (HLA) diversity, correlates of immune protection, and the applicability of different animal models must be answered. Finally, for HIV prevention efforts to have a global impact, effective, inexpensive, and easily administered regimens need to be developed, especially with regard to mother-infant transmission. NIAID is well positioned to tackle these scientific challenges through its vaccine, prevention, therapeutic, and basic research programs. Based on the current state of scientific knowledge, research plans in each of these areas complement each other to achieve NIAID's overall AIDS research goals to prevent the continued spread of HIV infection, and reduce the sickness and death associated with it. The specific objectives and strategies for accomplishing these goals are highlighted below. They are consistent with and draw upon the NIH-wide FY2000 Plan for HIV-Related Research and the draft FY2001 version of that plan.
Epidemiologic research provides information that advances our understanding of the biology and clinical course of HIV infection. NIAID's epidemiology studies focus on cohorts of individuals who are either at high risk for HIV infection or are already infected. These individuals are seen regularly and followed over long periods. Comprehensive data and biological sample collections provide a complete picture of HIV infection and disease, and serve as a unique resource for investigations of immunologic, virologic, genetic, and other factors that may modulate the various stages of HIV disease.
Understand the changing pattern of HIV infection throughout the world, and the impact of therapeutic, vaccine, and other prevention-based interventions on survival and clinical outcome.
Research Opportunities and Plans
- Identify and characterize the risk factors and mechanisms of HIV transmission in different parts of the world to understand why and how people continue to be infected with HIV.
- Determine the incidence and prevalence of adverse health outcomes, including cardiovascular diseases, diabetes, metabolic complications, opportunistic infections (OIs), and co-morbidity with other infections.
- Determine the role of host genetics in susceptibility to HIV infection, disease progression, and immune response.
- Determine the prevalence of drug-resistant HIV and its relationship to disease.
- Determine the epidemiology of treated patients, and the effects of therapeutic and preventive interventions on infection, morbidity, and mortality in domestic and international populations.
- Develop and evaluate improved methods for epidemiologic studies, including culturally relevant recruitment and retention approaches; improved laboratory, sampling, and statistical methods; and informatics.
- Conduct studies on the effects of highly active antiretroviral therapy (HAART) on virologic and immunologic markers of disease progression and long-term effects in diverse populations, including post-exposure and high-risk cohorts.
- Conduct epidemiologic studies to ascertain the prevalence of HIV-1 clades, HIV-2, tuberculosis, and hepatitis C.
- Conduct studies to determine the short-term, intermediate, and long-term effects of cost-effective antiretroviral therapy during pregnancy and after delivery, on the mother and newborn in domestic and international populations.
- Develop and maintain domestic and international infrastructures for epidemiology studies.
New and Continuing Programs
- Address the pathogenesis of disease progression among HIV-infected women and their children - Women and Infants Transmission Study (WITS).
Follow the long-term history of HIV-infected and at-risk individuals - Multicenter AIDS Cohort Study (MACS).
- Investigate the natural history of HIV infection in women in the United States - Women's Interagency HIV Study (WIHS).
- Study host immunogenetic characterization, including HLA types and T-cell epitopes - HLA Typing and Epitope Mapping to Guide HIV Vaccine Design Program.
HIV pathogenesis research increases our understanding of the biology of HIV by studying the virus' life cycle, virus-host interactions, and mechanisms of disease progression and transmission. NIAID supports HIV pathogenesis research investigating: mechanisms of viral entry and infection: the structure, function, and mechanism of action of viral genes and proteins; and studies of how the immune system responds to the virus. Knowledge gained from these studies enhances the ability of researchers to create new agents and vaccines to combat HIV infection. These efforts have yielded significant scientific information about HIV, including the identification of new structures for viral components of HIV, co-receptors, and the existence of multiple, persistent HIV reservoirs in human tissues. Despite these advances, questions still remain about the molecular interactions that regulate HIV expression and replication. More information is also needed about how the virus evades the immune system to identify additional targets for therapeutic interventions and vaccines.
Understand how HIV causes disease.
Research Opportunities and Plans
- Define the cells or tissues that serve as initial target sites of infection, the role of viral genotypes/phenotypes, and the HIV dose required for establishment of HIV infection.
- Define the mechanisms of HIV persistence in cell and tissue reservoirs, mechanisms of latent virus reactivation, and the impact of low-level viral replication on transmissibility.
- Define direct and indirect mechanisms of T-cell depletion, and enhance and expand innovative studies on human immunology to guide immune reconstitution and vaccine development efforts.
- Define the etiology and pathophysiology of treatment-related metabolic abnormalities in adults and children.
- Define the mechanisms underlying HIV-associated neurological disease and neurobehavioral dysfunction in adults and children.
- Define the pathogenic mechanisms of HIV-related opportunistic infections (OIs) in adults and children.
- Identify new viral and cellular targets for therapeutics, microbicides, and vaccine development based upon new insights into HIV biology and HIV-host interactions.
New and Continuing Programs
Support investigator-initiated, hypothesis-driven HIV/AIDS pathogenesis research.
Provide infrastructure and promote basic, clinical, behavioral, and translational AIDS research at institutions that receive significant AIDS funding from multiple NIH Institutes or Centers - Centers for AIDS Research (CFAR).
- Examine molecular and cellular biology, virology, and immunology in animal models, human cohorts, or patient samples - Mechanisms of AIDS Pathogenesis: Collaborative Teams (MAPS).
- Study HIV-1 pathogenesis utilizing data and biological specimens from and coordinated with the Multicenter AIDS Cohort (MACS) Pathogenesis Research Laboratories.
- Study mechanisms of mother-to-infant HIV-1 transmission and pathogenesis of HIV-1 infection in infants and children - Mechanisms And Pathogenesis Of Pediatric HIV-1 Infection.
- Formulate and test specific hypotheses for HIV/AIDS pathogenesis in women - HIV Pathogenesis in Women's Interagency HIV Study.
- Provide state-of-the-art biological and chemical materials to support HIV research - NIH AIDS Research and Reference Reagent Program, including the NIAID Tetramer Facility.
- Support repositories for specimens from HIV epidemiology, therapeutic, vaccine, and other prevention research studies.
- Support pathogenesis research on acute and early HIV-1 infection - Acute Infection and Early Disease Research Program.
NIAID-sponsored therapeutics research has had a dramatic impact on the clinical management of HIV infection over the past decade. NIAID clinical trials networks have defined international guidelines for: (1) the treatment of primary HIV infection and associated opportunistic infections; (2) prophylactic regimens for secondary infections; (3) biological markers, such as CD4+ counts and HIV-1 viral load for predicting drug effectiveness and disease progression; and (4) the use of antiretroviral drugs for preventing mother-to-infant transmission. More recent studies have shown that highly active antiretroviral therapy (HAART) regimens of at least three antiretroviral drugs, (i.e., reverse transcriptase inhibitors and usually at least one protease inhibitor) is capable of suppressing HIV viral load to undetectable levels in many infected individuals and partially restoring immune function. Such regimens have had a dramatic impact on HIV morbidity and mortality in this country. Nonetheless, treatment failures occur as a result of the development of resistance and/or non-adherence to complicated and often toxic regimens. Moreover, damage to the immune system is not fully reversed. Thus, there is an ongoing, urgent need for new therapeutic agents to control HIV replication and boost, rebuild, and/or replace immunity lost in HIV infection.
- Extend the gains in survival and quality of life achieved by current therapy by minimizing the adverse effects of long-term treatment and, ultimately, to cure HIV infection.
Research Opportunities and Plans
- Optimize antiretroviral therapy for untreated and pretreated HIV-infected patients to minimize development of drug resistance, enhance tolerability, contain costs, and improve long-term patient outcomes.
- Determine the regional and global patterns of resistance to antiretroviral therapies and its impact on long-term antiretroviral treatment efficacy, and develop effective therapies for individuals with drug-resistant HIV.
- Develop and evaluate new agents and treatment strategies to destroy or inhibit the expression of HIV in tissue reservoirs and latently infected cells.
- Develop and evaluate therapeutic approaches to enhance, restore, and/or maintain the immune systems of HIV-infected individuals. Determine whether HIV-directed immune responses can be augmented in infected individuals, and if so, whether it benefits the patient.
- Define the structure and function of potential molecular targets and agents for the prevention and treatment of HIV-associated opportunistic infections (OIs), including drug-resistant tuberculosis, Mycobacterium avium complex (MAC), cytomegalovirus, Pneumocystis carinii, and hepatitis C virus.
- Develop strategies for assessing, preventing, and treating HIV nervous system infection and central and peripheral nervous system disorders in HIV-infected individuals.
- Develop and evaluate improved therapies for the treatment and prevention of serious HIV-associated complications, including metabolic and body composition disorders, wasting syndrome, growth failure, and other systemic manifestations.
- Determine the safety of antiviral agents in pregnant women, including transplacental passage of agents and fetal safety.
- Determine in newborns the pharmacokinetics, metabolism, tissue absorption, and elimination of antiviral drugs.
- Develop improved mechanisms for assessment of long-term outcomes in clinical trial settings.
- Develop long-term drug trials targeted at acute and early HIV infection.
- Reduce the complexity of treatment regimens and develop strategies to improve treatment adherence.
- Define biological markers associated with effectiveness and durability of response to therapies to permit individualization of therapies and simplification of clinical trial design in an era of diminishing clinical endpoints.
- Develop strategies for promoting effective health care utilization among persons with HIV infection. Promote modifications in the health care delivery system to better serve the testing and treatment needs of disenfranchised and culturally diverse populations.
- Develop international collaborations to assist in answering critical therapeutic questions by including populations of HIV-infected patients outside the United States and in developing countries.
New and Continuing Programs
Evaluate innovative therapeutic strategies and interventions for adults with HIV/AIDS and its complications, including opportunistic infections (OIs) and neurological disorders associated with HIV/AIDS Adult AIDS Clinical Trials Group (AACTG).
- Conduct clinical trials in adults to evaluate the long-term benefits and unintended consequences of various treatment strategies - Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).
- Evaluate the efficacy of drugs and drug combinations for treating HIV infection and HIV-associated illnesses in infants, children, adolescents, and pregnant women - Pediatric AIDS Clinical Trials Group (PACTG).
- Support preclinical discovery and development of new and improved therapeutics - Novel HIV Therapies: Integrated Preclinical/Clinical Program and HIV Therapeutics: Targeting Research Gaps.
- Support chemical and biological databases, pharmacology, toxicology, analytical chemistry, and drug manufacturing for the development of new HIV therapeutics - Chemistry and Pharmaceutical Resources for Therapeutics Development Program.
- Provide tissue-based small animal models for HIV drug discovery, and in vitro virologic and immunologic evaluations for anti-HIV drugs and microbicides - In Vitro and Animal Model Testing Resources for Therapeutics Development Program.
- Support development of new therapies to treat AIDS- and cancer-associated opportunistic infections (OIs) - National Cooperative Drug Discovery Research on Opportunistic Infections.
- Support development of new strategies for the prevention and treatment of complications of HIV and HIV therapy - Therapeutics Research on AIDS-Associated Opportunistic Infections and Collaborations for Advanced Strategies in Opportunistic Infections and HIV-Associated Complications.
- Support acquisition, screening, and animal model testing of potential therapeutics, screening for activity in microbiological systems and animal models of tuberculosis, and assistance with development and licensing of candidate drugs without corporate sponsorship - NIAID Tuberculosis Drug Development.
HIV/AIDS Vaccine Coordinating Activities
NIAID is the principal in all substantial federal HIV/AIDS vaccine coordinating activities. These committees are lead by +12 senior NIAID officials. Dr. Anthony S. Fauci, NIAID Director, heads the AIDS Vaccine Subcommittee of the Committee on Health and Safety and Food Research and Development, of the White House's National Science and Technology Council. He also leads the Public Health Service Subcommittee on AIDS Vaccine Development. Dr. Peggy Johnston, NIAID's Assistant Director for HIV/AIDS Vaccines, chairs the NIH Office of AIDS Research Coordinating Committee on HIV Vaccines.
The discovery and development of a vaccine that protects against HIV infection is one of the highest priorities of the NIH AIDS research program. A great challenge of vaccine research is the need for contributions from a variety of disparate fields of science (e.g., basic science, empiric animal testing, human trials) to develop an efficacious vaccine. NIAID's comprehensive vaccine program has led to a number of significant scientific advances. NIAID-supported researchers have made strides in elucidating the structure of HIV, understanding the role of the immune system in controlling HIV, improving vaccine antigenicity, and developing new and better animal models for testing candidate vaccines. To accelerate identification of effective vaccine candidates, future studies will need to address the significance of latently infected cells, immune responses induced by current vaccine candidates, and the impact of HIV and HLA diversity. In addition, because the majority of new HIV infections are occurring in the developing world, strong international collaborations will need to be formed and ethical issues addressed in order to conduct efficacy studies in those countries. The coordination of this complex program of AIDS vaccine research is an important function of NIAID.
Identify and develop safe, effective vaccines to protect people from HIV infection and disease.
Research Opportunities and Plans
- Identify mechanisms of protective immunity and host defense to HIV in adults, newborns, and infants, and develop assays to measure these immune responses.
- Build upon recent knowledge regarding the establishment of HIV infection to develop and test a broad range of new vaccine strategies, alone or in combination, to induce selective immune responses (e.g., humoral, cellular, mucosal, and systemic) against primary non-syncitium inducing virus and CCR5-using HIV isolates from all genetic clades.
- Design viral antigens and vaccine delivery methods that elicit long-lasting protective immune responses against a broad range of HIV isolates by applying findings from basic, epidemiological, and clinical research.
- Develop and utilize simian-human chimeric viruses (SHIV) with different degrees of virulence to more closely reflect disease progression in humans and the genetic variation observed worldwide.
- Improve animal models and the availability of non-human primates for systematic, comparative efficacy testing of vaccine concepts; improve understanding of the protection mechanisms that might be translated to HIV vaccine studies in humans; and evaluate candidate vaccine strategies in animal models.
- Identify domestic and foreign populations in which to define and assess seroincidence and genetic subtypes, as well as determine and optimize feasibility of vaccine studies in appropriate cohorts.
- Conduct domestic and international vaccine trials in populations at risk for HIV transmission via different routes.
- Advance the most promising candidate vaccines to Phase 1 and Phase 2 clinical trials and, if safe and immunogenic, then to larger, Phase 3 trials to determine efficacy.
- Evaluate how or whether individuals at high risk for HIV infection alter their behavior as a result of participating in a vaccine trial.
- Identify and develop broadly effective, polyvalent anti-HIV functional antibody combinations or other products for prophylaxis of HIV transmission alone or in combination with vaccination and/or short-term antiretroviral prophylaxis.
- Develop safe and effective vaccine strategies and passive immune interventions for preventing or controlling HIV infection in newborns and infants worldwide.
- Open NIAID programs to international researchers to ensure the best approaches worldwide are pursued vigorously by the best researchers possible.
- Foster early and continued collaboration with industry on research and development of candidate vaccines, and test a broad array of vaccine concepts and combinations of different approaches for potential HIV vaccine products, including vaccines for particular populations.
- Coordinate NIAID research efforts with the NIH Vaccine Research Center (VRC).
- Develop strategies, infrastructure, and collaborations with governments and communities to ensure adequate performance of vaccine trials, while balancing the prevention needs of at-risk populations.
New and Continuing Programs
- Support investigator-initiated HIV vaccine research.
- Carry out a comprehensive HIV vaccine research agenda focused on the clinical evaluation of promising HIV vaccine candidates - HIV Vaccine Trials Network (HVTN).
- Encourage the entrance of novel and innovative vaccine discovery and development concepts into the research pipeline - Innovation Grant Program: Approaches in HIV Vaccine Research.
- Support investigator-initiated HIV vaccine research where investigators have collected significant preliminary data - HIV Vaccine Research and Design (HIVRAD) Program.
- Support development and production of HIV vaccines for clinical trials - HIV Vaccine Production Contract.
- Provide procurement and/or production of reagents essential to AIDS vaccine development and evaluation, as well as quality assurance testing of these reagents -Vaccine Reagent Resource.
- Support laboratory-to-clinic development, evaluation, and refinement of vaccine concepts - Integrated Preclinical/Clinical AIDS Vaccine Development.
- Support consortia of scientists to advance vaccine concepts toward a vaccine product within a five-year period - HIV Vaccine Design and Development Teams.
- Compile, analyze, and disseminate HIV genetic sequence and associated data worldwide - HIV Database and Analysis Unit.
- Provide non-human primates for immunization with candidate SIV or HIV vaccines - Simian Vaccine Evaluation Units.
- Support the development of methods for evaluating immune responses to vaccines - Laboratory Methods to Assess Responses To HIV Vaccine Candidates.
- Support research on the human mucosal immune system relevant to the design of HIV vaccines and other preventions - Mucosal Immunity in Pathogenesis/Prevention of Human Disease.
Non-Vaccine Prevention Strategies
The AIDS epidemic continues to take its toll worldwide, despite major advances in understanding the pathogenesis and treatment of HIV infection. Control of the epidemic will probably require a combination of prevention strategies to protect against HIV infection, even in the presence of an efficacious vaccine. Such strategies include methods to interrupt mother-to-infant transmission of HIV; biomedical approaches, such as topical microbicides and the treatment of sexually transmitted diseases (STDs); and behavioral interventions. Given the global dimensions of the epidemic and urgent need to find methods to halt transmission worldwide, NIAID supports a range of prevention research activities in both domestic and international settings.
- Identify safe, efficacious, cost-effective non-vaccine interventions to prevent the transmission of HIV.
Research Opportunities and Plans
- Develop biomedical strategies to inhibit transmission of HIV through exposure to HIV-containing blood, tissues, and other fluids. Candidate strategies include topical microbicides, HIV-specific virucides, and systemic antiretroviral agents.
- Develop biomedical strategies to interrupt vertical transmission of HIV from mother to child in developed and developing countries, and in breastfeeding and non-breastfeeding populations using interventions that are widely affordable, accessible, and practical in those populations.
- Identify host, gender, extrinsic and viral factors and cofactors, including other STDs, that affect HIV transmission, and assess interventions to slow viral transmission in at-risk domestic and international populations.
- Develop and evaluate effective social and behavioral interventions at the society, community, organization, social network, dyadic, and individual levels to prevent HIV transmission and acquisition by reducing risk behaviors and increasing protective behaviors. Interventions should address the risks in their social and cultural contexts both domestically and internationally.
- Identify the determinants, processes, cultural and contextual issues influencing infection-related risk and protective behaviors, and the consequences and impact of HIV disease, including treatment for and management of HIV infection.
- Develop and evaluate strategies to prevent or minimize the negative physical, cognitive, and social consequences of HIV, including stigmatization of persons with or at risk for HIV infection.
New and Continuing Programs
- Conduct domestic and international research on promising biomedical and behavioral strategies for the prevention of HIV transmission HIV Prevention Trials Network (HPTN).
- Evaluate interventions designed to reduce mother-to-infant transmission of HIV-1 - Pediatric AIDS Clinical Trials Group (PACTG).
Conduct multidisciplinary biomedical and behavioral research in disease mechanisms, vaccines, diagnosis, and treatment - Sexually Transmitted Disease Cooperative Research Centers.
- Evaluate candidate topical microbicides in preclinical studies and clinical trials, and develop behavioral interventions to ensure acceptance and use of topical microbicides - Topical Microbicide Program Projects.
- Support the preclinical development of topical microbicides - In Vitro, Animal Model, Chemical and Pharmaceutical Resources Program.
Research Program Publications
http://www.nih.gov/od/oar/public/pubs/fy2000pln.pdf The National Institutes of Health FY2000 Plan for HIV-Related Research.
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