Human endothelial cells enhance human immunodeficiency virus type 1 replication in CD4+ T cells in a Nef-dependent manner in vitro and in vivo

Jaehyuk Choi, Jason Walker, Sergei Boichuk, Nancy Kirkiles-Smith, Nicholas Torpey, Jordan S. Pober, Louis Alexander*

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 CB4+ 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 ia 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.

Original languageEnglish (US)
Pages (from-to)264-276
Number of pages13
JournalJournal of virology
Volume79
Issue number1
DOIs
StatePublished - Jan 1 2005

Fingerprint

Virus Replication
Human immunodeficiency virus 1
endothelial cells
HIV-1
Endothelial Cells
T-lymphocytes
T-Lymphocytes
Antigen-Presenting Cells
antigen-presenting cells
Coculture Techniques
coculture
T-Cell Antigen Receptor
In Vitro Techniques
Major Histocompatibility Complex
major histocompatibility complex
SCID Mice
receptors
cardiovascular system
Cardiovascular System
Dendritic Cells

ASJC Scopus subject areas

  • Immunology

Cite this

Choi, Jaehyuk ; Walker, Jason ; Boichuk, Sergei ; Kirkiles-Smith, Nancy ; Torpey, Nicholas ; Pober, Jordan S. ; Alexander, Louis. / Human endothelial cells enhance human immunodeficiency virus type 1 replication in CD4+ T cells in a Nef-dependent manner in vitro and in vivo. In: Journal of virology. 2005 ; Vol. 79, No. 1. pp. 264-276.
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Human endothelial cells enhance human immunodeficiency virus type 1 replication in CD4+ T cells in a Nef-dependent manner in vitro and in vivo. / Choi, Jaehyuk; Walker, Jason; Boichuk, Sergei; Kirkiles-Smith, Nancy; Torpey, Nicholas; Pober, Jordan S.; Alexander, Louis.

In: Journal of virology, Vol. 79, No. 1, 01.01.2005, p. 264-276.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Human endothelial cells enhance human immunodeficiency virus type 1 replication in CD4+ T cells in a Nef-dependent manner in vitro and in vivo

AU - Choi, Jaehyuk

AU - Walker, Jason

AU - Boichuk, Sergei

AU - Kirkiles-Smith, Nancy

AU - Torpey, Nicholas

AU - Pober, Jordan S.

AU - Alexander, Louis

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N2 - 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 CB4+ 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 ia 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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