VPAC1 is a cellular neuroendocrine receptor expressed on T cells that actively facilitates productive HIV-1 infection.

Abstract

OBJECTIVE:

A 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.

METHODS:

Reverse 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 by gag p24 ELISA using HIV-1IIIB or by luciferase activity using pseudo envelope-typed HXB2-NL4-3-luciferase. Analysis of HIV-1 gag DNA and 2-LTR circles was utilized to examine a possible mechanism for the effect of VPAC1.

RESULTS:

Using VPAC1 signal blocking antibody, we showed that up to 80% of productive infection with HIV-1IIIB was 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 facilitated in vitro infection with HIV-1 HXB2-NL4-3. Analysis of HIV-1 gag DNA 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.

CONCLUSION:

We 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.

• Authors: Donald R Branch, Linda J E Valenta, Shida Yousefi, Darinka Sakac, Ruchi Singla, Meenakshi Bali, Beni M Sahai, Xue-Zhong Ma
• Journal: AIDS (London, England) (AIDS) Vol. 16 Issue 3 Pg. 309-19 (Feb 15 2002) ISSN: 0269-9370 [Print] England
• PMID: 11834941 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Antisense
• DNA, Complementary
• HIV Envelope Protein gp120
• Receptors, Vasoactive Intestinal Peptide
• Receptors, Vasoactive Intestinal Polypeptide, Type I

Topics

• Base Sequence
• Cell Line
• DNA, Antisense (genetics, pharmacology)
• DNA, Complementary (genetics)
• Gene Expression
• HIV Envelope Protein gp120 (immunology)
• HIV Infections (etiology, prevention & control)
• HIV Long Terminal Repeat
• HIV-1 (pathogenicity)
• Humans
• Jurkat Cells
• Receptors, Vasoactive Intestinal Peptide (antagonists & inhibitors, genetics, physiology)
• Receptors, Vasoactive Intestinal Polypeptide, Type I
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• T-Lymphocytes (physiology, virology)