Low TRBP levels support an innate human immunodeficiency virus type 1 resistance in astrocytes by enhancing the PKR antiviral response.
Acute human immunodeficiency virus type 1 (HIV-1) replication in astrocytes produces minimal new virus particles due, in part, to inefficient translation of viral structural proteins despite high levels of cytoplasmic viral mRNA. We found that a highly reactive double-stranded (ds) RNA-binding protein kinase (PKR) response in astrocytes underlies this inefficient translation of HIV-1 mRNA. The dsRNA elements made during acute replication of HIV-1 in astrocytes triggers PKR activation and the specific inhibition of HIV-1 protein translation. The heightened PKR response results from relatively low levels of the cellular antagonist of PKR, the TAR RNA binding protein (TRBP). Efficient HIV-1 production was restored in astrocytes by inhibiting the innate PKR response to HIV-1 dsRNA with dominant negative PKR mutants, or PKR knockdown by siRNA gene silencing. Increasing the expression of TRBP in astrocytes restored acute virus production to levels comparable to those observed in permissive cells. Therefore, the robust innate PKR antiviral response in astrocytes results from relatively low levels of TRBP expression and contributes to their restricted infection. Our findings highlight TRBP as a novel cellular target for therapeutic interventions to block productive HIV-1 replication in cells that are fully permissive for HIV-1 infection.
Ong
Chi L
CL
Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
Thorpe
Janine C
JC
Gorry
Paul R
PR
Bannwarth
Sylvie
S
Jaworowski
Anthony
A
Howard
Jane L
JL
Chung
Sean
S
Campbell
Shahan
S
Christensen
Helen S
HS
Clerzius
Guerline
G
Mouland
Andrew J
AJ
Gatignol
Anne
A
Purcell
Damian F J
DF
D001253:Astrocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D015536:Down-Regulation; D015497:HIV-1 / Q000254:growth & development* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099253:Trans-Activation Responsive RNA-Binding Protein
D016601:RNA-Binding Proteins; D019892:eIF-2 Kinase; D000099253:Trans-Activation Responsive RNA-Binding Protein