VPAC1 is a cellular neuroendocrine receptor expressed on T cells that actively facilitates productive HIV-1 infection
作者:
Donald Branch,
Linda Valenta,
Shida Yousefi,
Darinka Sakac,
Ruchi Singla,
Meenakshi Bali,
Beni Sahai,
Xue-Zhong Ma,
期刊:
AIDS
(OVID Available online 2002)
卷期:
Volume 16,
issue 3
页码: 309-319
ISSN:0269-9370
年代: 2002
出版商: OVID
关键词: VPAC1;HIV-1;modulation of infection;therapeutic target;2-LTR circles
数据来源: OVID
摘要:
ObjectiveA lack of productive HIV-1 infection of Kit225 compared to Jurkat T cells, despite similar levels of CD4 and HIV-1 chemokine co-receptors, was found to correlate with the expression of vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide receptor-1 (VPAC1). We therefore examined a role for this seven-transmembrane G protein-coupled neuroendocrine receptor in modulating HIV-1 infection.MethodsReverse transcription–PCR was used to show the level of VPAC1 expression in different T-cell lines. A signal-blocking antibody to VPAC1 was used to examine its inhibiting effect on HIV-1 infection. Transfection of VPAC1 cDNA in both sense and anti-sense orientation was used to assess the role of VPAC1 in HIV-1 infection. HIV-1 infection was monitored bygagp24 ELISA using HIV-1IIIBor by luciferase activity using pseudo envelope-typed HXB2-NL4-3-luciferase. Analysis of HIV-1gagDNA and 2-LTR circles was utilized to examine a possible mechanism for the effect of VPAC1.ResultsUsing VPAC1 signal blocking antibody, we showed that up to 80% of productive infection with HIV-1IIIBwas inhibited. We also demonstrated that HIV-1 gp120 has sequence similarity to the natural ligand for VPAC1 and postulate that it can activate this receptor directly. Transfection of VPAC1 cDNA in the anti-sense orientation resulted in a significant loss, up to 50% of productive infection. In contrast, transfection of cells with VPAC1 in the sense orientation increased the productive infection by more than 15-fold and caused a profound increase in syncytium formation. Furthermore, stimulation of VPAC1 on primary cells facilitatedin vitroinfection with HIV-1 HXB2-NL4-3. Analysis of HIV-1gagDNA indicated that VPAC1 does not affect viral entry; however, cells that show negligible expression of VPAC1 may not be productively infected as indicated by a lack of 2-LTR circle formation.ConclusionWe have discovered a cellular receptor, VPAC1, that is a novel and potent facilitator of HIV-1 infection and thus, is a potentially important new target for therapeutic intervention.
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