Infected cell killing by HIV-1 protease promotes NF-kappaB dependent HIV-1 replication.
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.
Bren
Gary D
GD
Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, United States of America.
Whitman
Joe
J
Cummins
Nathan
N
Shepard
Brett
B
Rizza
Stacey A
SA
Trushin
Sergey A
SA
Badley
Andrew D
AD
D056769:Alstrom Syndrome; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology; D053181:Caspase 8 / Q000235:genetics; D002470:Cell Survival; D004789:Enzyme Activation; D017930:Genes, Reporter; D016325:HIV Long Terminal Repeat / Q000235:genetics; D016333:HIV Protease / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000502:physiology*; D010957:Plasmids; D013601:T-Lymphocytes / Q000821:virology; D014162:Transfection; D014779:Virus Replication
D016328:NF-kappa B; D053181:Caspase 8; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1