HIV Protease Cleavage of Procaspase 8 is Necessary for Death of HIVInfected Cells

Andrew D Badley,Stacey A Rizza,Zilin Nie,Gary D Bren

doi:10.2174/1874357900802010001

Abstract

Numerous host and viral factors are capable of causing death of HIV infected cells, uninfected bystander cells, or both. We assessed the relevance of HIV protease in infected cell killing by mutating its obligate substrate for death, procaspase 8. VSV pseudotyped HIV infection of cells expressing WT caspase 8 resulted in apoptotic cell death and generation of the HIV protease specific cleavage product of procaspase 8, casp8p41. Conversely, both cell death and casp8p41 production were inhibited in cells expressing procaspase 8 engineered to be resistant to HIV protease cleavage. Lymph nodes from HIV-infected patients with ongoing viral replication also selectively expressed casp8p41, which colocalized with both infected and apoptotic cells. HIV protease cleavage of procaspase 8 appears to be a necessary event for infected cell killing, which is responsible for infected cell death within lymphoid tissues from HIV-infected patients.

Highlights

Numerous factors associated with HIV infection are capable of causing cell death
HIV protease cleavage of procaspase 8 appears to be a necessary event for infected cell killing, which is responsible for infected cell death within lymphoid tissues from HIV-infected patients
It is noteworthy that even under the conditions examined, 10-15% apoptosis was observed, and the authors acknowledged that HIV infection may directly cause loss of mitochondrial transmembrane potential and release of apoptogenic factors, similar to what has subsequently been described for HIV Vpr [4]

Summary

Introduction

Numerous factors associated with HIV infection are capable of causing cell death These can be categorized as viral proteins capable of initiating or modifying cell death pathways including Tat, env, Vpr and protease or host factors which are modified in a manner which favors cell death including Fas/Fas ligand, TNF/TNF receptor 1, and/or TRAIL/TRAIL receptor 1 or 2 (reviewed in [1]). Unlike the situation with uninfected cell death, the molecular stimuli responsible for infected cell death are even less well understood Such death has been variably described as being lytic or direct cytotoxicity, the majority of the investigations conclude that infected cells die through apoptosis as evidenced by caspase activation, TUNEL positivity, PARP cleavage, etc (reviewed in [2]).

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