The Biology of AIDS

Critical Scientific Questions for AIDS Research

HIV Pathogenesis

1. What are the molecular interactions involved in the reproduction of HIV and regulation of HIV expression?
2. What are the events at the cellular and organ system levels that characterize the course of HIV infection?
3. How do various genotypic and phenotypic viral factors affect the course of HIV infection, and what are their mechanisms and infection?
4. What host factors are important in regulating the expression of HIV or affecting the course of HIV infection, and what are their mechanisms of action?
5. How do cofactors affect the course of HIV infection, and what are their mechanisms of action?
6. What are the direct and indirect mechanisms of HIV-mediated immunodeficiency?
7. How can animal models be used to understand HIV-mediated pathogenesis?
8. What are the mechanisms of sexual/mucosal transmission of HIV?

Epidemiology and Natural History

1. What clinical, behavioral, and environmental factors are associated with HIV transmission in adults, and what trends in transmission are apparent?
2. What clinical and pathological outcomes are seen in the populations most affected by HIV infection, and what trends in natural history are apparent?
3. What clinical, behavioral, and environmental factors predict rapid or indolent progression of immunologic dysfunction and/or clinical disease?
4. What epidemiologic research must be done prior to the initiation of large-scale HIV vaccine/prevention trials?

Vaccine Research and Development

1. What can be learned from the natural immune response to HIV and other animal model infections to guide the development of an effective HIV vaccine?
2. What is the relevance of the genetic variation of HIV to vaccine development?
3. How important is the local mucosal immune response for protection against HIV infection/disease? If important, what are its characteristics? How can it be optimally elicited?
4. What viral components and vaccine delivery methods are required to elicit a protective immune response?
5. What adjuvant strategies are useful in optimizing the quantitative or qualitative nature of the immune response to an HIV vaccine?
6. How can animal models be improved and their use optimized?
7. What has been/can be learned about development of an effective HIV vaccine from phase I/II studies in (1) low-risk and high-risk individuals, (2) maternal-fetal transmission, and (3) HIV-infected individuals?
8. What must be done to prepare for phase III efficacy trials and show that they are feasible?
9. What information concerning particular vaccine candidates is needed before deciding to initiate phase III efficacy trials? How will the progress of specific candidates be monitored and guided?

Therapeutics Research and Development

Primary Disease Therapeutics

1. Can the therapeutic index of existing and/or approved anti-HIV therapy be improved through the use of novel combinations of agent combinations of agents, alternative dosage schedules, or improved drug formulations, including antiviral and immunomodulators in combination?
2. What are the implications and strategies for management of viral resistance to antiretroviral therapy?
3. What are the potential benefits/risks of treating acute/early HIV infection?
4. What immune-based strategies for treatment of HIV disease be developed?
5. What identification and validation of surrogate endpoints be developed for use in monitoring therapy and expediting the development of new approaches to therapy?

Treatment and prevention of HIV-Related Opportunistic Infections

1. Cytomegalovirus: What can be done to improve treatment or prevention of HIV-associated CMV disease?
2. Infectious Causes of Diarrhea and Wasting: What are the most important infectious causes of HIV-associated diarrhea and wasting and what preventative measures or treatment can be developed?
3. Mycobacterium avium Complex (MAC): What approaches can be discovered and developed to improve treatment and/or prevention of MAC infection in people with HIV disease?
4. Mycobacterium tuberculosis: What can be done to improve treatment and/or prevention of disease caused by Mycobacterium tuberculosis infection, both drug-sensitive and -resistant forms, among patients with HIV disease and health care workers caring for them? How can delivery of currently available and effective drugs be improved?
5. Pathogenic Fungi (Cryptococcus, Histoplasm, Candida albicans): What can be done to improve therapy and prophylaxis for infection and disease caused by the pathogenic fungi associated with HIV disease?
6. Pneumocystis carinii Pneumonia (PCP): What can be done to improve therapy and prophylaxis of Pneumocystis carinii infection and disease?
7. Simultaneous Prophylaxis of Multiple Opportunistic Pathogens: What approaches can be developed to provide effective, safe, and tolerable simultaneous prophylaxis against multiple opportunistic infections?
8. Toxoplasma gondii: What can be done to improve treatment or prevention of HIV-associated central nervous system disease caused by Toxoplasma gondii?

Oncology

1. What can be done to best facilitate the development of better therapeutic strategies to treat Kaposi's sarcoma and lymphoma?

Neurology

1. What can be done to best facilitate the development of better diagnostic/evaluative tools and therapeutic strategies for the neurologic manifestations of HIV disease?

Pediatric HIV Disease

Perinatal Transmission

1. What are the mechanisms and timing of perinatal transmission of HIV?
2. Can prenatal, intrapartum, and/or postnatal interventions interrupt maternal-infant transmission?

Early Diagnosis

1. How can early, definitive diagnosis of HIV infection in fetuses and infants best be accomplished?

Prevention of Horizontal Transmission

1. How can horizontal transmission of HIV to adolescents be prevented?

Pediatric Natural History/Pathogenesis

1. How does HIV disease affect the development of organ systems such as the cardiovascular, central nervous, endocrine, and immune systems of infants and young children?
2. What is responsible for the observed wide variation in the rate of disease progression in pediatric patients with HIV infection?

Therapy

1. What strategies should be followed to evaluate HIV-related therapies in children?
2. What high priority questions should be addressed in clinical trials of antiretroviral agents in pediatric patients?
3. How can opportunistic infections in children be prevented and treated?
4. How can active and/or passive immunotherapy be applied to the treatment of pediatric HIV disease?

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