Infected Cell Killing by HIV-1 Protease Promotes NF-κB Dependent HIV-1 Replication

• Published in: PloS one 2008-05, Vol.3 (5), p.e2112
• Main Authors: Bren, Gary D., Whitman, Joe, Cummins, Nathan, Shepard, Brett, Rizza, Stacey A., Trushin, Sergey A., Badley, Andrew D.
• Format: Article
• Language: English
• Subjects: Amino acids; Apoptosis; Caspase; Caspase-8; CD4 antigen; Cell activation; Cleavage; Cloning; Glycoproteins; HIV; Human immunodeficiency virus; Infections; Infectious diseases; Infectious Diseases/HIV Infection and AIDS; Infectious Diseases/Sexually Transmitted Diseases; Infectious Diseases/Viral Infections; Kinases; Lymphocytes; Lymphocytes T; Mutagenesis; NF-κB protein; Phosphorylation; Plasmids; Protease; Proteinase; Proteins; Replication; Virology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0002112

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.