NIH Research Goals
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Goal #3 To conduct and support preclinical and clinical research to develop, test, and optimize treatments for HIV infection, HIV-associated conditions, and for the prevention of HIV transmission.
Objective #1

Improve understanding of the structure and function of molecular targets in order to develop improved assays for such targets; conduct screening, discovery, and preclinical development of novel anti-HIV agents and strategies (such as gene transfer technology and interruption of transmission) directed to the virus and/or host cell; and foster activity by and in collaboration with industry.


Identify and develop novel anti-HIV therapies, particularly those therapies that impact at different stages of the life cycle of the virus.

Action Steps
  1. Identify and characterize promising targets for anti-HIV therapy and extend knowledge of their mechanisms of action, develop relevant assays for identifying drugs active against those targets, and develop new compounds active at those targets, with emphasis placed on identifying agents active at novel targets other than reverse transcriptase inhibitors; emphasize agents that can effectively cross the blood-brain barrier.
  2. Complete preclinical development, in cooperation with industry when appropriate, of promising new compounds and combinations of compounds and novel natural products, including assessment of toxicity, immunologic effects, pharmacokinetics, teratogenicity, and fertility in animal models and development of analytical method and chemical formulations.
  3. Continue and accelerate domestic and international collection screening of large numbers of natural and synthesized compounds for anti-HIV activity, with a particular emphasis on the detection of agents that act at unique steps of the HIV life cycle with the intent of identifying lead compounds that can be modified for increased potency and other attributes (such as bioavailability and central nervous system penetration); develop and screen combinatorial libraries.
  4. Emphasize basic and applied research to advance cross-NIH development of gene therapy; support development of preclinical laboratories to advance gene therapies; advance gene therapies, including new strategies for streamlining or eliminating ex vivo manipulation of cells; develop more efficient and safe viral and non-viral gene delivery vectors; target tissue cells and subcellular compartments; develop effective antiviral genes; standardize evaluation of different gene therapies singly and in combination; and develop suitable lentivirus animal models for in vivo efficacy and safety studies.
  5. Determine the high-resolution molecular structures for several of the HIV proteins and apply these structures to the rational design of drugs as part of the targeted drug development program; determine generalizable and effective approached for the use of macromolecular structure in designing drugs to combat HIV infection and AIDS; make resolved structures available in publicly accessible data bases.
  6. Increase understanding of the mechanisms and limitations of drug resistance; study the effect of various agents on HIV replication and viral variation; evaluate early markers of resistance; evaluate the activity of anti-HIV drugs in various cell types (including macrophages) and in various stages of the cell cycle.
  7. Develop new compounds capable of inhibiting the sexual transmission of HIV, such as topical microbicides (which may inhibit HIV and STDs associated with enhanced HIV transmission), HIV-specific viricides, and systemic agents.
  8. Develop formulations that would be suitable for infants and children for both existing and experimental agents.
  9. Evaluate transplacental passage of antiretroviral and other agents as well as the effects of these drugs on placental function and on the embryo/fetus in animal models.
Objective #2

Conduct clinical trials and develop new trial methodologies for the treatment of HIV infection. Trials should be designed in order to rapidly develop new therapeutic strategies, optimize clinical efficacy and proper use of available modalities, define factors that affect the success of therapeutic strategies (including the role of resistance), and advance our understanding of disease pathogenesis and progression.


Trials to evaluate new antiretroviral therapies alone and in combination will provide important information regarding resistance and synergistic effects of drugs that may eventually prolong the disease-free state and survival in HIV-infected individuals.

Action Steps
  1. Support and improve clinical trials of potential therapeutic agents and combinations of agents in studies to determine pharmacokinetics and bioavailability and evaluate anti-HIV combinations that are non-cross-resistant, synergistic, and toxicity-sparing and that may delay development of drug-resistant HIV strains; enhance collaboration between and within ICDs to facilitate opportunities for clinical trials.
  2. Implement the development and evaluation of virologic, immunologic, and clinical markers to assess drug activity and determine the prognostic value of surrogate markers in response to therapeutic interventions.
  3. Support research and development of clinical trials methodology and study design so that appropriate pathways are taken rapidly to evaluate the activity, clinical efficacy, and ultimate acceptability of new agents and approaches that translate into clinical use.
  4. Increase the understanding of the pathogenesis of HIV disease based on the evaluation of antiretroviral agents in clinical trials; establish effective mechanisms to evaluate therapeutic interventions and elucidate the pathogenesis of acute/early HIV infection.
  5. Foster collaboration and better interactions with industry in drug development and evaluation efforts.
  6. Evaluate safety, toxicity, and pharmacokinetics of retroviral agents provided to pregnant women, including transplacental passage of the agent, safety to the fetus/infant, and pharmacokinetics of drug elimination in the newborn. (Also noteworthy, assess the potential efficacy and feasibility of obstetric interventions to prevent vertical transmissions, such as cesarean deliveries and other aspects of intrapartum care.)
  7. Enhance utilization of General Clinical Research Centers (GCRCs) for the conduct of single and multi-institutional clinical trials.
  8. Develop and validate quality-of-life parameters included in patient assessments of clinical trials.
  9. Support research on the effectiveness of pharmacologic (including compliance with therapies and STD prevention) and non-pharmacologic including psychosocial) interventions (including nutritional factors and adherence improvement).
  10. Investigate possible interactions between therapies for HIV-related disease and other substances that HIV-infected individuals might use, such as drug-abuse treatment medications, oral contraceptives or other prescription drugs, nonprescription drugs, alternative or complementary therapies, or drugs of abuse.
  11. Coordinate studies to encourage co-enrollment of patients on all trials where appropriate (co-enrollment would not only allow for better utilization of limited resources but also enable assessment of concomitant medications and their interactions, improving the efficiency of the primary study).
  12. Develop a coordinated plan to evaluate long-term therapeutic strategies, e.g., develop plans for long-term follow-up, enroll patients in sequential randomized trials once they have reached an end point in their initial trial.
  13. Support clinical trials to evaluate the safety and pharmacokinetics of existing and experimental agents for use in treating HIV-infected infants and children; evaluate the effects of puberty on the pharmacokinetics of antiretroviral agents and other drugs for the treatment/prophylaxis of HIV infection and the pharmacokinetics of drugs in adolescents.
  14. Evaluate potential late toxic effects of antiretroviral therapy given to infants and children.
Objective #3

Develop and evaluate strategies that will enhance, restore, and/or maintain the immune systems of HIV-infected individuals and extend our understanding of immunopathogenesis.


Essential to HIV research efforts are studies directed toward finding therapies that can restore, enhance, or maintain the integrity of the immune system.

Action Steps
  1. Evaluate therapeutic approaches that test specific hypotheses of HIV immunopathogenesis.
  2. Develop and validate new methods for evaluating immune function in the context of clinical trials.
  3. Continue and accelerate the testing of cytokines, modulators of cytokines, and other immunomodulating agents either singly or in combination with antiretroviral agents for the purpose of reconstituting the deficient immune systems of HIV-infected individuals.
  4. Develop and evaluate various approaches of active and passive immunotherapy for both HIV infection and its sequelae.
  5. Develop a program of reconstituting the immune systems of HIV-infected individuals by administration of cellular elements in an autologous, syngeneic, or allogeneic fashion, including use of expanded peripheral blood T cells, bone marrow transplantation, thymic transplantation, cord blood, stem cells, and/or xenogeneic transplantation.
  6. Develop new therapeutic strategies based on gene therapy approaches to protect hematopoietic stem cells and thereby reconstitute the immune system with HIV-resistant lymphoid, monocytic and other cellular compartments.
  7. Use structural biologic techniques to determine the structures of various cytokines and cytokine receptors as potential targets for HIV therapies.
  8. Increase collaboration of ICDs by joint funding of projects to facilitate the conduct of immune-based therapeutic trials and to enhance pathogenesis-related research in HIV-infected individuals.
  9. Foster collaboration and better interactions with industry in developing and evaluating immunorestorative/immune-enhancing agents.
  10. Define the mechanisms of immunomodulating agents and proceed with preclinical studies of the most promising agents.
Objective #4

Discover, develop, and evaluate potential agents for prevention and treatment of HIV-associated OIS and other infections modified by HIV infection.


Opportunistic infections (OIs) are the most common cause of morbidity and mortality in HIV-infected individuals. Continuing to develop and evaluate therapies for preventing and treating OIs is essential for decreasing morbidity and improving survival.

Action Steps
  1. Support basic research on OIs in order to increase fundamental knowledge and to identify new therapeutic targets and strategies and understand how pathogens contribute to morbidity.
  2. Determine the high resolution molecular structures for OI proteins and apply these structures to the rational design of drugs as part of the targeted drug development program and determine generalizable and effective approaches for the use of macromolecular structure in designing drugs to combat OIs associated with AIDS.
  3. Support discovery and preclinical programs to develop therapies especially targeting cryptosporidia, microsporidia, JC virus, HPV, and azole-resistant fungal organisms, with emphasis on bioavailable agents with favorable pharmacokinetics.
  4. Develop in vitro culture systems for OIs such as Pneumocystis carinii (PCP).
  5. Further conduct clinical trials for the prophylaxis and treatment of HIV-associated OIs in HIV-infected individuals.
  6. Important OIs include Mycobacterium tuberculosis infection (TB), Mycobacterium avium complex, cytomegalovirus infection, cryptosporidiosis, microsporidiosis, cryptococcal disease, azole-resistant fungal infection, toxoplasmosis, PCP, acyclovir-resistant herpes infections, progressive multifocal leukoencephalopathy (PML), bacterial infections, and other infections whose course is affected by HIV.
  7. Evaluate immune-based therapies as adjuncts for treating OIs.
  8. Determine the optimal strategies and combinations of agents to prevent and treat multiple OIs (by simultaneous prophylaxis of multiple opportunistic pathogens) and determine their effects in combination with antiretroviral agents.
  9. Strategies need to focus on the subgroups at increased risk, time of initiation, compliance, pharmacologic interactions, toxicities and adverse reactions (e.g. trimethoprim sulfamethoxazole reactions), and minimizing development of resistance; studies should include quality-of-life assessments and cost-benefit analyses.
  10. Develop and utilize animal models for preclinical efficacy, pharmacokinetics, and safety testing of potential agents for OIs, including mutagenicity and teratogenicity.
  11. Develop clinically useful assays for the rapid diagnosis of disease, treatment response, and sensitivity testing of OIs, especially TB, MAI, enterics, and infections produced by CMV, fungi, Toxoplasma, and JC virus, including use of specimens in existing repositories.
  12. Determine the role and capability of preexisting immunity (both induced and natural) to control OIs and the ability of HIV-infected individuals to respond to vaccination throughout the course of infection and disease; assess possible interaction of vaccination and HIV replication.
  13. Explore the bidirectional interactions between OIs and HIV infection including possible impact of opportunistic pathogens on the clinical expression and acceleration of HIV disease and vice versa.
  14. Support clinical trials to evaluate the safety and pharmacokinetics of existing and experimental agents for use in preventing and treating OIs in HIV-infected infants, children, and pregnant women.
Objective #5

Develop, evaluate, and implement strategies for interrupting vertical transmission of HIV from mother to child and extend out understanding of perinatal transmission and the pathogenesis of early infection (treatment of children will be addressed in other objectives).


Vertical transmission of HIV from mother to child is the predominant mode of transmission for pediatric HIV infection. The identification, development, and testing of interventions should be based on the pathogenesis of transmission.

Action Steps
  1. Support the rapid translation of basic research observations to strategies for the interruption of vertical transmission; apply the results of clinical trials to the investigation of pathogenesis and to clinical practice.
  2. Support national and international collaborative studies to retrospectively and prospectively evaluate potential obstetric factors associated with vertical transmission including non-protocol use of antiretroviral agents.
  3. Develop and evaluate strategies for interrupting the vertical transmission of HIV from pregnant women to their offspring that are simpler and less costly than the current AZT regimen and derive information on pathogenesis of transmission from the study of these strategies.
  4. Such strategies include antiviral agents, anti-HIV immunoglobulin, monclonal antibodies, vitamin supplementation (e.g. vitamin A), HIV vaccines, adjuvants, virucides, and other intrapartum interventions alone and in combination.
  5. Evaluate the safety, toxicity, pharmacokinetics, and antiretroviral activity of anti-HIV agents in pregnant women and newborns; explore the use of highly active agents that may develop resistance rapidly and could be used in this setting.
  6. Assess the potential efficacy and feasibility of obstetric interventions to prevent vertical transmissions, such as cesarean deliveries and other aspects of intrapartum care.
  7. Develop and improve sensitive and specific diagnostic parameters that are accessible and cost-effective to permit early differentiation of HIV infection status in children born to HIV-infected mothers.
  8. Investigate the role of the placenta in transmission of anti-HIV drugs from mother to fetus.
  9. Expand the obstetrical and pediatric infrastructure for the conduct of perinatal trials through collaborative efforts, particularly in the international setting.
  10. Support the long-term follow-up of women and children who participate in perinatal trials to evaluate potential distant effects of antiretroviral agents and/or biologics.
  11. Evaluate the risk of vertical transmission of drug-resistant virus. Evaluate incorporation of ACTG 076 AZT regimen into clinical practice in the United States.
  12. Evaluate therapeutic strategies for treating infants during acquisition of HIV to determine whether disease progression can be significantly altered.
Objective #6

Discover, develop, and evaluate improved strategies for the treatment and prevention of HIV-associated malignancies and extend our understanding of the risk factors for and pathogenesis of such malignancies.


HIV-associated malignancies have a significant impact on morbidity and mortality, and some are expected to become increasingly common as survival with sever immune dysfunction is prolonged and as the demographics of HIV infection change. The development of methods to identify persons at high risk for subsequent malignancy, and the identification, development, and clinical testing of new therapeutic strategies for these malignancies are essential.

Action Steps
  1. Support basic research on HIV-associated malignancies to increase fundamental knowledge of the etiology, pathogenesis, and biology of these neoplasms; develop preclinical models for testing potential therapeutic strategies.
  2. Identify novel mechanisms and targets (e.g. cytokines, angiogenesis, viral or hormonal co-factors) for treatment and prevention of HIV-associated tumors, including Kaposi's sarcoma (KS), non-Hodgkin's lymphoma, HPV-associated malignancies, and others, and develop new therapeutic strategies on the basis of these findings.
  3. Use structural biologic and biochemical information to rationally design drugs to inhibit specific pathogenic factors of HIV-associated malignancies.
  4. Develop in vivo models (SCID/nude mouse) for pathogenesis and drug sensitivity testing.
  5. Develop in vitro models of KS as well as assays for angiogenesis inhibitors.
  6. Encourage the develop and coordinate the conduct of clinical trials that concurrently evaluate antiretroviral and anti-OI therapeutic strategies directed against the malignancy in order to assess the effects of such treatment on the malignancy as well as on the underlying HIV infection, immune function, and clinical course.
  7. Continue and expand screening, discovery and development of novel therapeutic agents with activity against HIV-associated malignancies (e.g. agents with better CNS penetration, agents with better safety profiles).
  8. Develop trials to optimize existing therapies for malignancies in HIV-infected patients, including therapeutic adjuncts such as hematopoietic colony-stimulating factors and supportive care; develop and validate quality-of-life assessments.
  9. Encourage collaborative studies to develop mechanisms for early identification of patients at high risk for malignancy and to develop and assess interventional strategies to reduce or prevent the development of malignancies.
  10. Improve diagnostic methods for early diagnosis of malignancies and for early detection of recurrent cancer.
  11. Improve collaboration between various adult and pediatric cooperative groups conducting clinical trials of HIV-associated malignancies and ICDs and industry to accelerate trials completion and approval of active agents.
  12. Foster prompt referral of patients (co-registration) from antiretroviral trials to trials for AIDS-related malignancies.
Objective #7

Develop strategies for assessing, preventing, and treating central and peripheral nervous system dysfunction in the course of HIV infection.


Nervous system impairment, including AIDS-related cognitive/motor dysfunction (formerly AIDS dementia complex), and peripheral nerve/spinal cord dysfunction are serious sequelae of HIV disease.

Action Steps
  1. Develop novel strategies and agents that are active against putative pathways of HIV-induced CNS dysfunction, e.g inhibitors of quinolinic acid, excitatory neurotransmitters, gp160/120, and other potential neurotoxins.
  2. Implement studies related to the delineation of mechanisms responsible for impaired neurocognitive development in children born to HIV-infected mothers, and develop strategies directed at the prevention and treatment of this complication of HIV infection; utilize insights from the impaired state to better understand the course of normal neurocognitive development.
  3. Implement clinical trials addressing nervous system complications of HIV infection and incorporate neurologic and neuropsychological assessments into other HIV-related clinical trials.
  4. Develop therapeutic agents and/or delivery systems that are capable of crossing the blood-brain barrier and develop carriers that capitalize on different mechanisms to deliver drug to the CNS and are active against HIV infection; assess the safety of these different preparations; develop an understanding of physical and physiological mechanisms involved in penetration of the blood-brain barrier, and possibly develop agents that could conceivably block HIV entry into the CNS.
  5. Better delineate etiologies of peripheral neuropathy in HIV infection, and develop strategies to prevent and treat this complication.
  6. Develop and utilize in vitro and animal models of CNS impairment and AIDS-related cognitive/motor dysfunction to further identify agents that can reverse HIV neuropathogenesis.
  7. Implement assessments and approaches for the diagnosis of HIV-related dementia in clinical studies; improve implementation of standardized adult, adolescent, and pediatric neuropsychologic and neurologic assessment batteries in clinical studies and evaluate treatment-induced changes in neurocognitive impairment in a linguistically and culturally sensitive context.
  8. Develop alternative methods for detecting and assessing response to treatment of central and peripheral nervous system dysfunction including brain structural, spectroscopic, and functional imaging (for dementia); develop quantitative summary testing and examination of cutaneous nerve fibers in neuropathy.
Objective #8

Develop and evaluate therapies for the treatment and prevention of serious HIV-associated complications, especially wasting syndrome and growth failure, as well as other disorders including hematologic, dermatologic, renal, metabolic, pulmonary, and oral manifestations.


Important clinical sequelae of HIV infection include wasting syndrome, growth failure, metabolic disorders, dermatologic disorders, ITP, nephropathy, oral diseases, and other symptoms and serious complications. Drugs and strategies that can treat these sequelae are needed to ameliorate these conditions.

Action Steps
  1. Develop and evaluate therapeutic strategies for preventing and ameliorating the various sequelae of HIV infection (listed above in the Description) and increasing understanding of their pathogenesis.
  2. Develop and validate quality-of-life parameters for adults and children for the various sequelae of HIV infection (listed above in the Description).
  3. Develop and evaluate therapeutic strategies for alleviating the various symptoms of unclear etiology in HIV-infected persons (listed above in the Description) and improving the quality of life.
$ 463 million
$ 473 million
$ 470 million

All populations.


Researchers, clinicians, community and patient representatives, and NIH-affiliated advisory councils and committees.



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