Date of Award

10-12-2001

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Jun Ren

Abstract

A significant number of individuals diagnosed with acquired immune deficiency syndrome (AIDS) develop AIDS wasting syndrome (AWS). In these individuals, weight loss and endocrine dysfunction has been described. We previously developed a rat model for the study of a minor subset of the AWS population described as having an apparent growth hormone (GH) deficiency (Type I AWS) using the human immunodeficiency virus (HTV) envelope protein. gpl20, as the mediator. My goal was to develop a rat model for the study of the far more common form of AWS (Type II), which is characterized by a GHresistant state. Cultured, primary hepatocytes were treated with gpI20 to determine if it had any effect on basal or stimulated insulin-like growth factor (IGF-I) or insulinlike growth factor binding protein (IGFBP-3) secretion or IGF-I mRNA accumulation. Similar studies were conducted in a human hepatoma cell line (HepG2) to determine if gpl20 had any effect on IGFBP-l secretion. In determining if gpl20 could cause the weight loss described in AWS and/or alter the endocrine function as it related to the GH-IGF-I axis, rats were implanted with osmotic mini-pumps for the continuous infusion of gp!20 for a period of 2 weeks. Culturing systems were also developed for the coculture of hepatocytes with macrophages (Kupffer cells and RAW264.7 cells) to determine the role resident hepatic macrophage may play in the development of Type II AWS. gpl20 was unable to effect the basal or stimulated secretion of IGF-I or IGFBP-3 from rat hepatocytes. In the human cells (HepG2) however, gp 120 (100 and 1000 pM) was able to stimulate basal IGFBP-l secretion and reverse the inhibitory effect of insulin on IGFBP-l secretion. In vivo studies failed to show an effect of gpl20 (0.2 or 2.0 pg/day) on IGF-I or IGFBP-3 secretion or hepatic IGF-I mRNA accumulation but treatment with gpl20 did show a tendency to inhibit weight gain, when compared to vehicle controls, following surgery. In hepatocytes cocultured with macrophages. gpl20 failed to inhibit IGF-I or IGFBP-3 secretion and was unable to stimulate cytokine (II-IP) production.It would appear that gp 120 is able to mediate some of the effects on endocrine function observed in Type II AWS patients (weight and increased IGFBP-l secretion). However, due to the lack of access to large amounts of recombinant gpI20. increased doses and chronic exposure to the peptide have thus far been left uninvestigated. This makes the generation of transgenically engineered animal, expressing the gp 120 portion of the HIV env gene in the periphery, the next logical step in studying the role gpl20 may play in the development of the endocrine manifestation of Type II AWS.

Download

Share

COinS