HIV gp120 Induces, NF-κB Dependent, HIV Replication that Requires Procaspase 8

BACKGROUND: HIV envelope glycoprotein gp120 causes cellular activation resulting in anergy, apoptosis, proinflammatory cytokine production, and through an unknown mechanism, enhanced HIV replication. METHODOLOGY/PRINCIPAL FINDINGS: We 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/SIGNIFICANCE: Gp120 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.