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Journal of Virology, May 1999, p. 3968-3974, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Nef Enhances Human Immunodeficiency Virus Replication and Responsiveness to Interleukin-2 in Human Lymphoid Tissue Ex Vivo

Svetlana Glushakova,1 Jean-Charles Grivel,1 Kalachar Suryanarayana,2 Pascal Meylan,3 Jeffrey D. Lifson,2 Ronald Desrosiers,4,* and Leonid Margolis1,*

Laboratory of Molecular and Cellular Biophysics, National Institute of Child Health and Human Development, Bethesda, Maryland 208921; Laboratory of Retroviral Pathogenesis, AIDS Vaccine Program, SAIC Frederick, Frederick, Maryland 21702-12012; Institute of Microbiology, Centre Hospitalier Universitaite Vaudois, CH-1011 Lausanne, Switzerland3; and New England Regional Primate Research Center, Southborough, Massachusetts 01772-91024

Received 17 September 1998/Accepted 3 February 1999

The nef gene is important for the pathogenicity associated with simian immunodeficiency virus infection in rhesus monkeys and with human immunodeficiency virus type 1 (HIV-1) infection in humans. The mechanisms by which nef contributes to pathogenesis in vivo remain unclear. We investigated the contribution of nef to HIV-1 replication in human lymphoid tissue ex vivo by studying infection with parental HIV-1 strain NL4-3 and with a nef mutant (Delta nefNL4-3). In human tonsillar histocultures, NL4-3 replicated to higher levels than Delta nefNL4-3 did. Increased virus production with NL4-3 infection was associated with increased numbers of productively infected cells and greater loss of CD4+ T cells over time. While the numbers of productively infected T cells were increased in the presence of nef, the levels of viral expression and production per infected T cell were similar whether the nef gene was present or not. Exogenous interleukin-2 (IL-2) increased HIV-1 production in NL4-3-infected tissue in a dose-dependent manner. In contrast, Delta nefNL4-3 production was enhanced only marginally by IL-2. Thus, Nef can facilitate HIV-1 replication in human lymphoid tissue ex vivo by increasing the numbers of productively infected cells and by increasing the responsiveness to IL-2 stimulation.

* Corresponding author. Mailing address for L. Margolis: NIH, Bldg. 10, Rm. 10D14, Bethesda, MD 20892. Phone: (301) 594-2476. Fax: (301) 480-0857. E-mail: margolis{at}helix.nih.gov. Mailing address for R. Desrosiers: New England Regional Primate Research Center, Southborough, MA 01772-9102. Phone: (508) 624-8042. Fax: (508) 624-8190. E-mail: rdesrosi{at}warren.med.harvard.edu.

Journal of Virology, May 1999, p. 3968-3974, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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