Abstract
BackgroundHIV envelope glycoprotein gp120 causes cellular activation resulting in anergy, apoptosis, proinflammatory cytokine production, and through an unknown mechanism, enhanced HIV replication.Methodology/Principal FindingsWe describe that the signals which promote apoptosis are also responsible for the enhanced HIV replication. Specifically, we demonstrate that the caspase 8 cleavage fragment Caspase8p43, activates p50/p65 Nuclear Factor κB (NF-κB), in a manner which is inhibited by dominant negative IκBα. This caspase 8 dependent NF-κB activation occurs following stimulation with gp120, TNF, or CD3/CD28 crosslinking, but these treatments do not activate NF-κB in cells deficient in caspase 8. The Casp8p43 cleavage fragment also transactivates the HIV LTR through NF-κB, and the absence of caspase 8 following HIV infection greatly inhibits HIV replication.Conclusion/SignificanceGp120 induced caspase 8 dependent NF-κB activation is a novel pathway of HIV replication which increases understanding of the biology of T-cell death, as well as having implications for understanding treatment and prevention of HIV infection.
Highlights
The HIV env is a pleotrophic molecule which causes a range of effects on human cells, by ligating either the CD4 or chemokine receptors, env can cause activation, anergy, and/or apoptosis of the receptor bearing cell [1]
We assessed the impact of gp120 and other apoptosis inducers on HIV replication in primary CD4 T cells from HIV-infected patients (Figure 1C)
Our observations that caspase 8 is required for optimum Nuclear Factor kB (NF-kB) dependent gp120 mediated HIV LTR activation, and that the Casp8p43 cleavage product is a more potent activator of HIV LTR than full length caspase 8 offers insights into the biology of apoptosis
Summary
The HIV env is a pleotrophic molecule which causes a range of effects on human cells, by ligating either the CD4 or chemokine receptors, env can cause activation, anergy, and/or apoptosis of the receptor bearing cell [1]. Depending upon cell type and activation status, gp120 induced apoptosis can occur following CD4 crosslinking, or CXCR4 crosslinking, and despite early reports to the contrary, such apoptotic signaling cascades are caspase dependent [4,5,6]. Mitochondrial depolarization, release of cytochrome c, and formation of the apoptosome ensue [8]. This activates effector caspases 9 and 3, which function to activate initiator caspases such as caspase 8 to amplify the apoptotic cascade [9], and they cleave host regulatory and structural proteins which promote the phenotypic characteristics of apoptosis. HIV envelope glycoprotein gp120 causes cellular activation resulting in anergy, apoptosis, proinflammatory cytokine production, and through an unknown mechanism, enhanced HIV replication
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