AEGiS-11IAC: The role of the double stranded RNA dependent protein kinase PKR in HIV-1 pathogenesis.

11th International AIDS Conference


Vancouver, British Columbia — July 7-12, 1996

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The role of the double stranded RNA dependent protein kinase PKR in HIV-1 pathogenesis.

Int Conf AIDS 1996 Jul 7-12; 11:227 (abstract no. Tu.A.492)
Koromilas A, Nagai K, DeLuca C, Li S, Wong A, Cuddihy A, Tam N, Hiscott J; Lady Davis Institute, McGill Uiversity, Montreal, Canada. Fax: 514-340-7576. E-mail: mijh@musica.mcgill.ca.

OBJECTIVES: Replication of HIV-1 is inhibited by interferons (IFNs), and the IFN-induced, double stranded RNA dependent seine/threonine protein kinase (PKR) is thought to mediate this event by modulating protein synthesis. The objective of the present study was to examine the role of PKR in HIV-1 replication and in modulation of host signaling via the NF-KB pathway.

RESULTS: Ectopic expression of a mutant of PKR defective in RNA binding elicited intracellular events leading to an induction of HIV-1 replication in Jurkat cells. Specifically, expression of CD4, the major HIV-1 receptor, was induced by the PKR mutant at the transcriptional level. This induction of CD4 correlated with an increase in proviral DNA synthesis upon HIV-1 infection. Moreover, downmodulation of CD4 mRNA by HIV-1 was prevented in cells expressing the mutant of PKR. Also, to examine the molecular basis of constitutive NF-KB binding activity in HIV-1 infected cells, we analyzed the turnover of IKBa protein, the activity of PKR and the intracellular levels of NF-KB subunits in myeloid cell models. HIV-1 infection resulted in constitutive, low level expression of type 1 interferon (IFN) at the mRNA level. Constitutive PKR activity was also detected in HIV-1 infected cells, induced as a result of IFN production. Increased degradation of IKBa in HIV-1 infected cells may account for the constitutive DNA binding activity. Furthermore, a dramatic increase in c-Rel and NF-KB2 p100 was detected in HIV-1 infected cells relative to uninfected cells.

CONCLUSIONS: These findings suggest that modulation of PKR activity has important implications in HIV-1 infection through the regulation of CD4 expression and the NF-KB pathway. HIV-1 infection of myeloid cells induces IFN production and PKR activity, which in turn enhances IKBa phosphorylation and subsequent degradation. Enhanced turnover of IKBa and the accumulation of NF-KB/Rel proteins may contribute to the chronically activated state of HIV-1 infected cells.

Keywords: AEGIS, eIF-2 Kinase, HIV-1, HIV Infections, Protein-Serine-Threonine Kinases, Virus Replication, NF-kappa B, Antigens, CD4, Interferons, Phosphorylation, Jurkat Cells, Mutation, Human, virology, genetics, ICA11KWDaegis,eif-2kinase,hiv-1,hivinfections,protein-serine-threoninekinases,virusreplication,nf-kappab,antigens,cd4,interferons,phosphorylation,jurkatcells,mutation,human,virology,genetics,ica11

960707
TuA492

Copyright © 1996 - International AIDS Society (IAS). Reproduction of this abstract (other than one copy for personal reference) must be cleared through the IAS.