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Journal of Virology, September 2005, p. 11194-11204, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11194-11204.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Endothelial Cells Promote Human Immunodeficiency Virus Replication in Nondividing Memory T Cells via Nef-, Vpr-, and T-Cell Receptor-Dependent Activation of NFAT

Jaehyuk Choi,¹ Jason Walker,² Kristina Talbert-Slagle,³ Paulette Wright,⁴ Jordan S. Pober,^1,5,6,7 and Louis Alexander^3*

Section of Immunobiology,¹ Department of Genetics,² Department of Epidemiology and Public Health,³ Department of Pharmacology,⁴ Department of Pathology,⁵ Department of Dermatology,⁶ Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Connecticut⁷

Received 25 March 2005/ Accepted 1 June 2005

Human endothelial cells (ECs) enhance human immunodeficiency virus (HIV) replication within CD4⁺ memory T cells by 50,000-fold in a Nef-dependent manner. Here, we report that EC-mediated HIV type 1 replication is also dependent on an intact vpr gene. Moreover, we demonstrate that despite a requirement for engaging major histocompatibility complex (MHC) class II molecules and costimulators, EC-stimulated virus-producing cells (p24^high T cells) do not proliferate, nor are they arrested in the cell cycle. Rather, they are minimally activated, sometimes expressing CD69 but not CD25, HLA-DR, VLA-1, or effector cytokines. Blocking antibodies to interleukin 2 (IL-2), IL-6, IL-7, or tumor necrosis factor do not inhibit viral replication. Cyclosporine effectively inhibits viral replication, as does disruption of the NFAT binding site in the viral long terminal repeat. Furthermore, in the presence of ECs, suboptimal T-cell receptor (TCR) stimulation with phytohemagglutinin L supports efficient viral replication, and suboptimal stimulation with toxic shock syndrome toxin 1 leads to viral replication selectively in the TCR-stimulated, Vß2-expressing T cells. Collectively, these data indicate that ECs provide signals that promote Nef- and Vpr-dependent HIV replication in memory T cells that have been minimally activated through their TCRs. Our studies suggest a mechanism for HIV replication in vivo within the reservoir of circulating memory CD4⁺ T cells that persist despite antiretroviral therapy and further suggest that maintenance of immunological memory by MHC class II-expressing ECs via TCR signaling may contribute to HIV rebound following cessation of antiretroviral therapy.

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* Corresponding author. Mailing address: Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College St., New Haven, CT 06520. Phone: (203) 785-6917. Fax: (203) 785-7552. E-mail: louis.alexander{at}yale.edu.

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Journal of Virology, September 2005, p. 11194-11204, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11194-11204.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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