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Journal of Virology, November 1999, p. 9021-9028, Vol. 73, No. 11
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Inhibition of Replication of Reactivated Human Immunodeficiency Virus Type 1 (HIV-1) in Latently Infected U1 Cells Transduced with an HIV-1 Long Terminal Repeat-Driven PKR cDNA Construct

Nicholas F. Muto,1 Camille Martinand-Mari,2 Martin E. Adelson,1,dagger and Robert J. Suhadolnik1,2,*

Fels Institute for Cancer Research and Molecular Biology1 and Department of Biochemistry,2 Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Received 14 April 1999/Accepted 6 August 1999

Treatment of human immunodeficiency virus type 1 (HIV-1)-infected individuals with highly active antiretroviral therapy has effectively decreased viral load to undetectable levels. However, efforts to eliminate HIV-1 from these individuals have been unsuccessful, due to the presence of stable, latent viral reservoirs in resting and active CD4+ T lymphocytes and macrophages. These latent populations have become critical targets in the effort to eradicate HIV-1 from infected individuals. The mechanisms of HIV-1 latency have been studied by using the HIV-1-infected promonocytic cell line U1. The interferon-inducible double-stranded RNA-dependent p68 protein kinase (PKR), a key enzyme in the host-mediated antiviral response, is known to be down-regulated during HIV-1 infection. Therefore, in order to evaluate the role of PKR in the inhibition of replication of reactivated HIV-1 in latently infected U1 cells, we have utilized cDNA constructs containing PKR under the transcriptional control of the HIV-1 long terminal repeat. One PKR-transduced clone, U1/106-4:27, inhibited the tumor necrosis factor alpha (TNF-alpha )-induced replication of HIV-1 by 99% compared to control U1 cells as measured by syncytium formation and HIV-1 p24 antigen enzyme-linked immunosorbent assay. Western blot analysis showed an increase in PKR expression through 96 h postinduction in the U1/106-4:27 clone, concomitant with maximal increases in phosphorylation of the alpha  subunit of eukaryotic initiation factor 2 and NF-kappa B activity at 72 h postinduction. These results demonstrate that overexpression of PKR can inhibit the replication of reactivated HIV-1 in latently infected cells and confirm the involvement of PKR in the interferon-associated antiviral pathway against HIV-1 infection. Additionally, treatment of the PKR-transduced U1/106-4:27 clone with the protease inhibitor saquinavir (250 nM) completely inhibited TNF-alpha -induced HIV-1 replication.

* Corresponding author. Mailing address: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140. Phone: (215) 707-4607. Fax: (215) 707-3515. E-mail: rjs{at}astro.ocis.temple.edu.

dagger Present address: Department of Molecular Genetics and Microbiology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854.

Journal of Virology, November 1999, p. 9021-9028, Vol. 73, No. 11
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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