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PLoS One. 2008 May 7;3(5):e2112. doi: 10.1371/journal.pone.0002112.

Infected cell killing by HIV-1 protease promotes NF-kappaB dependent HIV-1 replication.

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Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, United States of America.


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-kappaB activation, (2) caspase 8 dependent apoptosis, and that (3) caspase 8 directly activates NF-kappaB, we questioned whether these three events might be interrelated. We first show that HIV-1 infected T cell apoptosis, NF-kappaB 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-kappaB activity. Finally, we demonstrate that the HIV protease cleavage of caspase 8 is necessary for optimal NF-kappaB activation and that the HIV-1 protease specific cleavage fragment Casp8p41 is sufficient to stimulate HIV-1 replication through NF-kappaB 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.

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