Multiple levels of PKR inhibition during HIV-1 replication.
Rev Med Virol
; 21(1): 42-53, 2011 Jan.
Article
em En
| MEDLINE
| ID: mdl-21294215
ABSTRACT
Recent therapeutic approaches against HIV-1 include IFN in combination therapy for patients with coinfections or as an alternative strategy against the virus. These treatment options require a better understanding of the weak efficacy of the IFN-stimulated genes, such as the protein kinase RNA-activated (PKR), which results in viral progression. Activated PKR has a strong antiviral activity on HIV-1 expression and production in cell culture. However, PKR is not activated upon HIV-1 infection when the virus reaches high levels of replication, due to viral and cellular controls. PKR is activated by low levels of the HIV-1 trans-activation response (TAR) RNA element, but is inhibited by high levels of this double-stranded RNA. The viral Tat protein also counteracts PKR activation by several mechanisms. In addition, HIV-1 replicates only in cells that have a high level of the TAR RNA binding protein (TRBP), a strong inhibitor of PKR activation. Furthermore, increased levels of adenosine deaminase acting on RNA (ADAR1) are observed when HIV-1 replicates at high levels and the protein binds to PKR and inhibits its activation. Finally, the PKR activator (PACT) also binds to PKR during HIV-1 replication with no subsequent kinase activation. The combination of all the inhibiting pathways that prevent PKR phosphorylation contributes to a high HIV-1 production in permissive cells. Enhancing PKR activation by counteracting its inhibitory partners could establish an increased innate immune antiviral pathway against HIV-1 and could enhance the efficacy of the IFN treatment.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Replicação Viral
/
Regulação para Baixo
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Infecções por HIV
/
HIV-1
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EIF-2 Quinase
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Rev Med Virol
Assunto da revista:
VIROLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Canadá