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Published online before print April 13, 2006

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(Journal of Leukocyte Biology. 2006;79:1328-1338.)
© 2006 by Society for Leukocyte Biology

HIV regulation of the IL-7R: a viral mechanism for enhancing HIV-1 replication in human macrophages in vitro

Mingjie Zhang^*, Jorg Drenkow, Carla S. R. Lankford, David M. Frucht, Ronald L. Rabin, Thomas R. Gingeras, Chettemegre Venkateshan^*, Franziska Schwartzkopff, Kathleen A. Clouse and Andrew I. Dayton^*,1

^* Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research & Review, and
Laboratory of Immunobiochemistry, DBPAP, Office of Vaccine Research and Review, Center for Biologics Evaluation & Research, U.S. Food and Drug Administration, Rockville, Maryland;
Affymetrix, Santa Clara, California; and
Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, Bethesda, Maryland

¹Correspondence: Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research & Review, Center for Biologics Evaluation & Research, FDA, HFM 315, CBER, 1401 Rockville Pike, Rockville, MD 20852-1448. E-mail: Dayton{at}cber.fda.gov

We report a novel mechanism, involving up-regulation of the interleukin (IL)-7 cytokine receptor, by which human immunodeficiency virus (HIV) enhances its own production in monocyte-derived macrophages (MDM) in vitro. HIV-1 infection or treatment of MDM cultures with exogenous HIV-1 Tat(86) protein up-regulates the IL-7 receptor (IL-7R) -chain at the levels of steady-state RNA, protein, and functional IL-7R on the cell surface (as measured by ligand-induced receptor signaling). This IL-7R up-regulation is associated with increased amounts of HIV-1 virions in the supernatants of infected MDM cultures treated with exogenous IL-7 cytokine. The overall effect of IL-7 stimulation on HIV replication in MDM culture supernatants is typically in the range of one log and greater. The results are consistent with a model in which HIV infection produces the Tat protein, which in turn up-regulates IL-7R in a paracrine manner. This results in increased IL-7R signaling in response to the IL-7 cytokine, which ultimately promotes early events in HIV replication, including binding/entry and possibly other steps prior to reverse transcription. The results suggest that the effects of IL-7 on HIV replication in MDM should be considered when analyzing and designing clinical trials involving treatment of patients with IL-7 or Tat vaccines.

Key Words: cytokine receptors • cytokines • Tat • AIDS

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