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Insights into simian immunodeficienc...

Overholser, Emily D.

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Insights into simian immunodeficiency virus-induced central nervous system disease: The role of the astrocyte and the endothelial cell.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Insights into simian immunodeficiency virus-induced central nervous system disease: The role of the astrocyte and the endothelial cell./
Author:	Overholser, Emily D.
Description:	140 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1675.
Contained By:	Dissertation Abstracts International65-04B.
Subject:	Biology, Microbiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3130754
ISBN:	0496780023

Insights into simian immunodeficiency virus-induced central nervous system disease: The role of the astrocyte and the endothelial cell.
Overholser, Emily D.

Insights into simian immunodeficiency virus-induced central nervous system disease: The role of the astrocyte and the endothelial cell. - 140 p.

Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1675.

Thesis (Ph.D.)--The Johns Hopkins University, 2004.

Human immunodeficiency virus (HIV) is a member of the lentivirus family of retroviruses that is estimated to have infected 40 million people worldwide by 2003. Twenty to thirty percent of HIV positive individuals will develop central nervous system (CNS) disease due to viral replication in the brain. The best animal model to study HIV and AIDS pathogenesis is the simian immunodeficiency virus (SIV) model in which infected macaques develop disease very similar to AIDS in humans. Further, 20--30% of SIV-infected animals develop CNS disease, similar to encephalitis in HIV-infected individuals. In order to enter the CNS and cause disease, HIV and SIV must somehow cross the blood-brain barrier (BBB), the relatively impermeable vasculature system in the brain comprised of endothelial cells stimulated by neighboring astrocyte foot processes to form tight junctions. Given the importance of these two cell types in maintaining BBB integrity and CNS homeostasis, the goal of this project was to analyze virus-cell interactions that occur between endothelial cells and astrocytes with both neurovirulent and non-neurovirulent SIV strains. Cell-free SIV was able to transmigrate across a confluent monolayer of primary and transformed endothelial cells in vitro, indicating that cell-free virus may be able to cross the endothelium of the blood-brain barrier without the need to "piggy-back" on trafficking immune cells. Interestingly, the studies described herein demonstrate that primary rhesus macaque astrocytes were susceptible to infection by neurovirulent SIV but not non-neurovirulent SIV. Viral replication in astrocytes was dependent upon the viral Nef protein for optimal and efficient replication. Moreover, macrophage-tropism was necessary but not sufficient for replication in primary astrocytes, and additional important amino acid sequences were required within the transmembrane portion of the viral Env protein to convert a CD4-dependent Env protein to a CD4-independent Env protein to facilitate entry into astrocytes. Thus, the data presented here strongly suggest that both endothelial cells and astrocytes play important roles in viral infection of the CNS and further elucidate several possible mechanisms by which these cells contribute to SIV neuropathogenesis and the development of encephalitis.

ISBN: 0496780023Subjects--Topical Terms:

1017734
Biology, Microbiology.

Insights into simian immunodeficiency virus-induced central nervous system disease: The role of the astrocyte and the endothelial cell.
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520 $a Human immunodeficiency virus (HIV) is a member of the lentivirus family of retroviruses that is estimated to have infected 40 million people worldwide by 2003. Twenty to thirty percent of HIV positive individuals will develop central nervous system (CNS) disease due to viral replication in the brain. The best animal model to study HIV and AIDS pathogenesis is the simian immunodeficiency virus (SIV) model in which infected macaques develop disease very similar to AIDS in humans. Further, 20--30% of SIV-infected animals develop CNS disease, similar to encephalitis in HIV-infected individuals. In order to enter the CNS and cause disease, HIV and SIV must somehow cross the blood-brain barrier (BBB), the relatively impermeable vasculature system in the brain comprised of endothelial cells stimulated by neighboring astrocyte foot processes to form tight junctions. Given the importance of these two cell types in maintaining BBB integrity and CNS homeostasis, the goal of this project was to analyze virus-cell interactions that occur between endothelial cells and astrocytes with both neurovirulent and non-neurovirulent SIV strains. Cell-free SIV was able to transmigrate across a confluent monolayer of primary and transformed endothelial cells in vitro, indicating that cell-free virus may be able to cross the endothelium of the blood-brain barrier without the need to "piggy-back" on trafficking immune cells. Interestingly, the studies described herein demonstrate that primary rhesus macaque astrocytes were susceptible to infection by neurovirulent SIV but not non-neurovirulent SIV. Viral replication in astrocytes was dependent upon the viral Nef protein for optimal and efficient replication. Moreover, macrophage-tropism was necessary but not sufficient for replication in primary astrocytes, and additional important amino acid sequences were required within the transmembrane portion of the viral Env protein to convert a CD4-dependent Env protein to a CD4-independent Env protein to facilitate entry into astrocytes. Thus, the data presented here strongly suggest that both endothelial cells and astrocytes play important roles in viral infection of the CNS and further elucidate several possible mechanisms by which these cells contribute to SIV neuropathogenesis and the development of encephalitis.
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