Acute HIV-1 infection of CD4 T cells often results in apoptotic death of infected cells, yet it is unclear what evolutionary advantage this offers to HIV-1. Given the independent observations that acute T cell HIV-1 infection results in (1) NF-κB activation, (2) caspase 8 dependent apoptosis, and that (3) caspase 8 directly activates NF-κB, we questioned whether these three events might be interrelated. We first show that HIV-1 infected T cell apoptosis, NF-κB activation, and caspase 8 cleavage by HIV-1 protease are coincident. Next we show that HIV-1 protease not only cleaves procaspase 8, producing Casp8p41, but also independently stimulates NF-κB activity. Finally, we demonstrate that the HIV protease cleavage of caspase 8 is necessary for optimal NF-κB activation and that the HIV-1 protease specific cleavage fragment Casp8p41 is sufficient to stimulate HIV-1 replication through NF-κB dependent HIV-LTR activation both in vitro as well as in cells from HIV infected donors. Consequently, the molecular events which promote death of HIV-1 infected T cells function dually to promote HIV-1 replication, thereby favoring the propagation and survival of HIV-1.
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.
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