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National Institutes of Health #2

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Goal #2

To conduct and support research to improve the understanding of HIV and the pathogenic mechanisms of HIV disease.

Objective #1

Delineate the cellular and molecular mechanisms associated with the viral immunopathogenesis of HIV-related immune dysfunction.

Action Steps
  1. Delineate the direct and indirect mechanisms underlying HIV-induced depletion and dysfunction of target cells/tissues.
  2. Define the virologic (load, phenotype, and genotype), immunologic (specific and nonspecific), pharmacologic, and environmental factors that contribute to disease progression and non-progression.
  3. Delineate the mechanisms of virally triggered immunopathogenesis, including immune activation, induction of nonresponsiveness, and production of host factors, including cytokines, in pathogenesis.
  4. Delineate the molecular mechanisms by which virus-encoded genes, gene products, and cellular factors regulate HIV replication and influence pathogenesis, with special emphasis on the use of primary virus isolates and cells.
  5. Delineate the mechanisms of host genetic factors that mediate resistance or sensitivity to infection and influence disease progression.
  6. Delineate the physiology and HIV-related pathophysiology of primary and secondary lymphoid organs, including hematopoietic precursor cells and their microenvironment.
  7. Study the mechanisms of HIV infection that uniquely influence the developing immune system.
  8. Further develop and utilize experimental models to examine the pathogenesis of lentiviral infections.
  9. Establish and expand programs to facilitate access to and sharing of key patient samples, animal model resources, laboratory reagents, information databases, and quantitative virologic and immunologic assays.

Basic scientific information regarding the cellular and molecular mechanisms that underlie HIV-related immune dysfunction and viral pathogenesis is critical to all areas of AIDS research.

Objective #2

Delineate the molecular and cellular mechanisms of transmission and establishment of infection and their impact on disease progression.

Action Steps
  1. Define the cellular and immune mechanisms that inhibit/enhance the early events in establishing HIV infection.
  2. Determine the impact of early events in the establishment of HIV infection on the clinical course of the disease.
  3. Determine the roles of specific and nonspecific mucosal and systemic immunity and other host factors that inhibit/enhance HIV transmission.
  4. Determine the cell or tissue type that serves as the portal of entry of HIV and the impact of STDs and other pathogenic processes that influence HIV transmission.
  5. Determine the role of viral phenotype/genotype and load on transmission of cell-free and cell-associated virus.
  6. Elucidate unique aspects of HIV transmission and disease progression in under-researched populations.
  7. Determine the mechanisms of vertical HIV transmission.

The mechanisms of HIV transmission and the early events in the establishment of infection, and their relationship to disease progression, need to be better understood.

Objective #3

Elucidate the etiologic factors and co-factors in the pathogenesis of AIDS-associated disease states. Enhance a bidirectional flow between basic and clinical observations and intervention programs ion HIV-related complications and foster interdisciplinary collaborations.


Knowledge of AIDS-associated disease pathogenesis is urgently needed.

Objective #3a

Elucidate the etiologic factors, co-factors, and mechanisms in the pathogenesis of HIV-related malignancies.


Knowledge about the origins and pathogenesis of HIV-related cancers is urgently needed.

Action Steps
  1. Elucidate the role of HIV infection, immune dysfunction, and interactions with potential co-factors in the development of HIV-associated malignancies.
  2. Identify the characteristics of the host that predispose to development of malignant disease, including genetic, hormonal, and growth factors and immunologic characteristics.
  3. Identify the pathogenic contributions of oncogenes, suppressor genes, carcinogens, and non-HIV viral and other microbial genes and proteins to HIV-associated malignancies; correlate these molecular factors with epidemiologic studies.
  4. Establish and expand programs to facilitate development and sharing of in vivo animal models and patient specimens for HIV-associated malignancies.
Objective #3b

Elucidate the pathogenic mechanisms involved in HIV-associated neurological disease and neurobehavioral dysfunction.


The damage that leads to both central and peripheral nervous system dysfunction must be better understood through studies of HIV-associated neuropathogenesis.

Action Steps
  1. Investigate the characteristics of lentiviruses that invade the nervous system and the mechanisms by which these viruses cause nervous system impairment.
  2. Study the effects of neurotrophins and immunoregulatory and proinflammatory cytokines on both host and viral gene expression.
  3. Employ animal models of CNS-lentivirus infection that are crucial to understanding neuropathophysiology.
  4. Delineate the role of OIs and drug treatment in neurologic complications of AIDS, including CNS dysfunction and peripheral neuropathies.
  5. Investigate biological and environmental factors that may affect nervous system function in the context of HIV-1 infection, emphasizing the role of psychoactive drug use.
  6. Study mechanisms of HIV infection that uniquely influence the developing nervous system.
  7. Develop technologies for correlative structural-functional analysis of progressive HIV-associated neurological and behavioral disorders and the progression of CNS disease.
Objective #3c

Elucidate the pathogenic mechanisms of HIV-related opportunistic infections.


It is critical to understand the pathogenic mechanisms responsible for the development of HIV-associated OIs.

Action Steps
  1. Elucidate the mechanisms of immune function that mediate protection against OIs.
  2. Study the effects of OIs on immune dysfunction and HIV disease progression.
  3. Conduct studies of the basic biology and pathogenic mechanisms of opportunistic pathogens and their interactions with the host.
  4. Develop in vitro techniques and animal models to propagate the opportunistic pathogens associated with HIV disease.
  5. Develop and validate diagnostic assays for the reliable and rapid identification of HIV-associated OIs.
  6. Identify biologic markers that are correlative for susceptibility and disease progression for HIV-associated OIs.
  7. Identify and elucidate the genetic and environmental risk factors associated with susceptibility to and development and progression of OIs.
Objective #3c

Elucidate the etiology and pathogenesis of HIV-related disorders: gastrointestinal, renal, endocrine, cardiovascular, cutaneous, hematologic, oral, pulmonary, and other diseases.


It is critical to understand various other organ/tissue-specific complications of HIV infection.

Action Steps
  1. Investigate the etiologic and pathogenic mechanisms of HIV-associated gastrointestinal disease.
  2. Identify the etiologic and pathogenic mechanisms of HIV-associated nephropathy.
  3. Elucidate the etiology and pathogenesis of endocrine dysfunction and the role of alteration in the endocrine/immune axis in progression of HIV disease.
  4. Elucidate the etiology and pathogenesis of HIV-related autoimmune disorders and cardiovascular, cutaneous, hematologic, oral, pulmonary, and other organ/tissue-specific disorders.
$ 344.3 million
$ 382.9 million
$ 400.2 million

All populations.


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NIH #1 - Appendix B: Research

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