Human endothelial cells enhance human immunodeficiency virus type 1 replication in CD4+ T cells in a Nef-dependent manner in vitro and in vivo.
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 naive 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.
Choi
Jaehyuk
J
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Walker
Jason
J
Boichuk
Sergei
S
Kirkiles-Smith
Nancy
N
Torpey
Nicholas
N
Pober
Jordan S
JS
Alexander
Louis
L
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000276:immunology*; D004730:Endothelium, Vascular / Q000166:cytology*; D015693:Gene Products, nef / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D000949:Histocompatibility Antigens Class II; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction; D014471:Umbilical Veins; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D000949:Histocompatibility Antigens Class II; D054311:nef Gene Products, Human Immunodeficiency Virus