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J Gen Virol 86 (2005), 765-771; DOI 10.1099/vir.0.80570-0

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© 2005 Society for General Microbiology

Short Communication

Nef expressed from human immunodeficiency virus type 1 extrachromosomal DNA downregulates CD4 on primary CD4+ T lymphocytes: implications for integrase inhibitors

Laura Gillim-Ross1,{dagger}, Andrea Cara2 and Mary E. Klotman1

1 Mount Sinai School of Medicine, Division of Infectious Diseases, 1 Gustave L. Levy Place, Box 1090, New York, NY 10029, USA
2 Laboratory of Virology, Istituto Superiore di Sanita, 00161 Roma, Italy

Correspondence
Mary E. Klotman
Mary.Klotman{at}mssm.edu

Recently developed integrase inhibitors targeting the HIV-1 integrase (IN) protein block integration of HIV DNA in the target cell, preventing subsequent virus replication. In the absence of integration, viral DNA is shunted towards the formation of extrachromosomal DNA (E-DNA). Although HIV-1 E-DNA does not support productive replication, it is transcriptionally active and produces viral proteins. However, the significance of E-DNA in virus replication and pathogenesis is poorly understood. In this study, the functional activity of the HIV-1 Nef protein expressed in the absence of viral integration was analysed. Using both a recombinant HIV-1 IN defective virus and a diketo acid IN inhibitor, evidence was provided showing that Nef expressed from E-DNA downregulates CD4 surface expression on primary CD4+ T lymphocytes. These results suggest that proteins expressed in the absence of integration may have potential clinical consequences, an issue that should be further explored with the introduction of IN inhibitors.

{dagger}Present address: Wadsworth Center, New York State Department of Health, Division of Infectious Diseases, 120 New Scotland Avenue, Albany, NY 12002, USA.




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