PEDIATRIC MONKEY MODEL FOR CYTOKINE THERAPY IN AIDS

Project: Research project

Project Details

Description

DESCRIPTION Of the infectious agents currently of clinical importance, HIV presents the greatest risk to the human female and her offspring. The clinical disease that occurs in HIV-infected children is similar to the adult, although infants infected with HIV have a more rapid clinical course with a higher rate of mortality. HIV infection results in aberrations in the hematopoietic system, although the mechanisms responsible for these findings are not known. The hematologic abnormalities associated with HIV infection are further exacerbated by AZT treatment, thereby limiting long-term use. Since antiretroviral therapies such as AZT can decrease virus load and increase survival, hematopoietic growth factors that can ameliorate myelosuppression have clinical utility. Growth factors such as stem cell factor (SCF) are known to induce proliferation of pluripotent progenitors, and studies have shown the differential effect of combining granulocyte-colony stimulating factor (G-CSF) with SCF for the recruitment of CD34+ stem cells in the peripheral circulation. Although the use of growth factors in combination with antiretroviral therapies is appealing, long-term toxicities are not known, clinical significance remains to be determined, and optimal methods for treatment have not been identified. Chronic stimulation could result in an increase in the number of targets for viral replication; effects may be intensified in gravid or young patients. The investigators propose to study the effects of administration of G-CSF and G-CSF+SCF in the simian immunodeficiency virus (SIV)-infected monkey model of pediatric AIDS. Studies are proposed with this model which will characterize the effects of systemic growth factor administration on hematopoiesis in the non- infected and SIV- infected fetus and dam (Specific Aim 1). Here, the investigators will administer G-CSF or G-CSF+SCF (+/- AZT) to gravid monkeys (second to third trimester) and evaluate (1) committed and noncommitted progenitors, (2) endogenous cytokine production, (3) immune response, and (4) virus load in the fetus and dam dynamically in specimens collected during gestation and at term. The investigators will also define the long-term effects of growth factor exposure on hematopoiesis and outcome of SIV-infection in utero (Specific Aim 2) by administering G-CSF or GCSF+SCF (+/- AZT) to infants infected with SIV in utero (pre- and postnatal growth factor administration or postnatal- birth to two months). Assessments of committed and noncommitted progenitors, endogenous cytokine production, immune response, and virus load will be evaluated in blood (pre- and postnatal) and bone marrow specimens, and tissues collected at necropsy (two months). These investigations will provide essential information in an animal model with similar reproductive and developmental features to the human, and will be directly applicable to the human fetus, infant, and gravid adult infected with HIV.
StatusFinished
Effective start/end date8/1/957/31/00

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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