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

Gary D Bren,Nathan Cummins,Sergey A Trushin,Joe Whitman,Brett Shepard,Andrew D Badley,Stacey A Rizza

doi:10.1371/journal.pone.0002112

Abstract

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.

Highlights

From a teleologic standpoint, it has been difficult to reconcile why a virally infected cell would undergo apoptosis, as it seems counter-intuitive that virus-initiated death of the host cell could offer a competitive advantage to that virus
HIV-1-induced activation of NF-kB is coincident with HIV1-induced cell death
It is established that acute HIV-1 infection of CD4 T cells results in both NF-kB activation as well as apoptotic cell death [12]

Summary

Introduction

It has been difficult to reconcile why a virally infected cell would undergo apoptosis, as it seems counter-intuitive that virus-initiated death of the host cell could offer a competitive advantage to that virus. The majority of HIV-1 encoded proteins are capable of initiating death of both HIV-1 infected cells as well as uninfected bystander cells. The expression of active HIV-1 protease within the cytoplasm of infected cells, coupled with the degenerate substrate specificity of HIV-1 protease, allows for host cell proteins to be substrates of HIV-1 protease [1]. Cleavage of one of these host substrates by protease, procaspase 8, is a necessary event for death of infected T cells [2]. Casp8p41 is specific to HIV-1 protease initiated apoptosis, and is not produced during apoptosis induced by either death receptor signaling nor mitochondriotoxic stress [2]. The relevance of Casp8p41 to infected cell death is suggested by mutational inhibition of HIV-1 protease cleavage of procaspase 8, which inhibits HIV-1 killing of infected cells [3]

Methods

Results

Conclusion