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J. Biol. Chem., Vol. 282, Issue 6, 3594-3604, February 9, 2007

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Hydroxyurea and Interleukin-6 Synergistically Reactivate HIV-1 Replication in a Latently Infected Promonocytic Cell Line via SP1/SP3 Transcription Factors^*

From the Laboratory of Human Retrovirology, Clinical Services Program, Science Applications International Corporation-Frederick Inc., NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702

The existence of viral latency limits the success of highly active antiretroviral therapy. With the therapeutic intention of reactivating latent virus to induce a cure, in this study we assessed the impact of cell synchronizers on HIV gene activation in latently infected U1 cells and investigated the molecular mechanisms responsible for such effect. Latently infected U1 cells were treated with 10 drugs including hydroxyurea (HU) and HIV-1 replication monitored using a p24 antigen capture assay. We found that HU was able to induce HIV-1 replication by 5-fold. HU has been used in the clinical treatment of HIV-1-infected patients in combination with didanosine; therefore, we investigated the impact of HU on HIV-1 activation in the presence of the proinflammatory cytokines, interleukin 6 (IL-6) and tumor necrosis factor- (TNF-). IL-6 or TNF- alone induced HIV replication by 18- and 500-fold, respectively. Of interest, in the presence of HU, IL-6-mediated HIV-1 activation was enhanced by >90-fold, whereas TNF--mediated activation was inhibited by >30%. A reporter gene assay showed that HU and IL-6 synergized to activate HIV promoter activity via the Sp1 binding site. Electrophoretic mobility shift and supershift assays revealed increased binding of the Sp1 and Sp3 transcription factors to this region. Western blot analysis showed that HU and IL-6 co-stimulation resulted in increased levels of Sp1 and Sp3 proteins. In contrast, treatment with HU plus TNF- down-regulated the expression of NF-B. These findings suggest that Sp1/Sp3 is involved in controlling the HU/IL-6-induced reactivation of HIV-1 in latently infected cells.

Received for publication, August 24, 2006 , and in revised form, November 15, 2006.

^* This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health Contract N01-CO-12400. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory of Human Retrovirology, Clinical Services Program, SAIC-Frederick Inc., NCI-Frederick, P. O. Box B, Bldg. 550, Rm. 126, Frederick, MD 21702. Tel.: 301-846-5450; Fax: 301-846-6762; E-mail: timamichi{at}mail.nih.gov.

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