TY - JOUR
T1 - Infected cell killing by HIV-1 protease promotes NF-κB dependent HIV-1 replication
AU - Bren, Gary D.
AU - Whitman, Joe
AU - Cummins, Nathan
AU - Shepard, Brett
AU - Rizz, Stacey A.
AU - Trushin, Sergey A.
AU - Badley, Andrew D.
PY - 2008/5/7
Y1 - 2008/5/7
N2 - Acute HIV-1 infection of CD4 T cells often results in apoptotic death of infected cells, yet 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-LRT 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.
AB - Acute HIV-1 infection of CD4 T cells often results in apoptotic death of infected cells, yet 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-LRT 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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U2 - 10.1371/journal.pone.0002112
DO - 10.1371/journal.pone.0002112
M3 - Article
C2 - 18461165
AN - SCOPUS:47749152622
SN - 1932-6203
VL - 3
JO - PloS one
JF - PloS one
IS - 5
M1 - e2112
ER -