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Journal of Virology, January 2005, p. 264-276, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.264-276.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human Endothelial Cells Enhance Human Immunodeficiency Virus Type 1 Replication in CD4⁺ T Cells in a Nef-Dependent Manner In Vitro and In Vivo

Section of Immunobiology,¹ Department of Genetics,² Department of Pathology,⁴ Department of Dermatology,⁵ Interdepartmental Program in Vascular Biology and Transplantation,⁶ Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut,⁷ Department of Pathophysiology, Kazan State Medical University, Kazan, Russia³

Received 4 May 2004/ Accepted 1 September 2004

Infected CD4⁺ T cells are the primary sites of human immunodeficiency virus type 1 (HIV-1) replication in vivo. However, signals from professional antigen-presenting cells (APCs), such as dendritic cells and macrophages, greatly enhance HIV-1 replication in T cells. Here, we report that in cocultures, vascular endothelial cells (ECs), which in humans can also serve as APCs, can enhance HIV-1 production of both CCR5- and CXCR4-utilizing strains approximately 50,000-fold. The observed HIV-1 replication enhancement conferred by ECs occurred only in memory CD4⁺ T cells, required expression of major histocompatibility complex class II (MHC-II) molecules by the ECs, and could not be conferred by fixed ECs, all of which are consistent with a requirement for EC-mediated T-cell activation via T-cell receptor (TCR) signaling. Deletion of nef (Nef^–) decreased HIV-1 production by approximately 100-fold in T cells cocultured with ECs but had no effect on virus production in T cells cocultured with professional APCs or fibroblasts induced to express MHC-II. Human ECs do not express B7 costimulators, but Nef^– replication in CD4⁺-T-cell and EC cocultures could not be rescued by anti-CD28 antibody. ECs act in trans to enhance wild-type but not Nef^– replication and facilitate enhanced wild-type replication in naïve T cells when added to T-cell or B-lymphoblastoid cell cocultures, suggesting that ECs also provide a TCR-independent signal to infected T cells. Consistent with these in vitro observations, wild-type HIV-1 replicated 30- to 50-fold more than Nef^– in human T cells infiltrating allogeneic human skin grafts on human huPBL-SCID/bg mice, an in vivo model of T-cell activation by ECs. Our studies suggest that ECs, which line the entire cardiovascular system and are, per force, in frequent contact with memory CD4⁺ T cells, provide signals to HIV-1-infected CD4⁺ T cells to greatly enhance HIV-1 production in a Nef-dependent manner, a mechanism that could contribute to the development of AIDS.

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