The HIV-1 glycoprotein gp120 elevates NF-kB levels in human cardiomyocytes which may be reversed with the treatment of a sesquiterpene lactone isolated from Vernonia staehelinoides
Date
2010-03-03T12:06:48Z
Authors
Coopusamy, Dayaneethie
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Abstract
Twenty five years of studying HIV-1 structure and replication have improved
diagnosis and treatment of individuals infected with the virus. In particular, the
introduction of highly active antiretroviral therapy (HAART) has significantly altered
the course of HIV-1 infection by increasing life expectancy and reducing
opportunistic infections. However, chronic cardiovascular complications such as HIV
associated cardiomyopathy (HIVCM), which manifest later during the course of HIV-
1 infection, have become increasingly evident. Despite its growing incidence, with
high cardiovascular morbidity and mortality in young and middle-aged adults, the
molecular mechanisms of HIVCM remain poorly understood. A number of pathways
have been implicated in HIVCM, including damage initiated by HIV-1 surface
glycoprotein, gp120, and dysregulation of NF-κB. NF-κB is a universal transcription
factor and it regulates a number of genes, many of which are involved in
inflammation, injury and stress response. The ability of HIV-1 to manipulate host
signalling pathways, including elevated NF-κB levels, has resulted in efficient viral
replication and gene expression. The elevation of NF-κB has also been shown to be
involved in animal models of HIVCM but very little work has been conducted on
human cells. For this reason, the primary objectives of this thesis were to establish the
level of NF-κB in a cellular model of HIVCM by challenging human cardiomyocytes
with HIV-1 or gp120 and to mitigate the effect on NF-κB using natural compounds derived from South African indigenous plants. The effect of gp120 and HIV-1 on NF-
κB levels in human cardiomyocytes was tested by an ELISA-based assay and
immunocytochemistry. This was to determine whether the damage induced by HIV-1
and gp120 is mediated by NF-κB. The results shows that gp120 significantly
increased NF-κB levels in human cardiomyocytes compared to control unstimulated
cardiomyocytes (p<0.001). One plant compound, the sesquiterpene lactone 106A,
significantly reduced the NF-κB response by human cardiomyocytes to gp120
stimulation (p<0.05). Taken together, this study suggests that the activation of NF-κB
by gp120 has a role to play in a cellular model of HIVCM and that the sesquiterpene
lactone 106A could prove valuable in further studies on the modulation of cellular
responses due to gp120 and HIV-1 induced stress in human cardiomyocytes