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J Virol. 2014 Jun;88(12):6672-89. doi: 10.1128/JVI.00825-14. Epub 2014 Apr 2.

HIV-1 Tat protein induces PD-L1 (B7-H1) expression on dendritic cells through tumor necrosis factor alpha- and toll-like receptor 4-mediated mechanisms.

Author information

1
INSERM, U1043, Toulouse, France CNRS, U5282, Toulouse, France Université Paul Sabatier Toulouse, Toulouse, France.
2
Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
3
INSERM, U1043, Toulouse, France CNRS, U5282, Toulouse, France Université Paul Sabatier Toulouse, Toulouse, France Department of Infectious Diseases, Toulouse University Hospital, Toulouse, France.
4
INSERM, U1043, Toulouse, France CNRS, U5282, Toulouse, France Université Paul Sabatier Toulouse, Toulouse, France Department of Virology, CHU Purpan, Toulouse, France.
5
INSERM, U1043, Toulouse, France CNRS, U5282, Toulouse, France Université Paul Sabatier Toulouse, Toulouse, France bahraoui@cict.fr.

Abstract

Chronic human immunodeficiency virus type 1 (HIV-1) infection is associated with induction of T-cell coinhibitory pathways. However, the mechanisms by which HIV-1 induces upregulation of coinhibitory molecules remain to be fully elucidated. The aim of the present study was to determine whether and how HIV-1 Tat protein, an immunosuppressive viral factor, induces the PD-1/PD-L1 coinhibitory pathway on human dendritic cells (DCs). We found that treatment of DCs with whole HIV-1 Tat protein significantly upregulated the level of expression of PD-L1. This PD-L1 upregulation was observed in monocyte-derived dendritic cells (MoDCs) obtained from either uninfected or HIV-1-infected patients as well as in primary myeloid DCs from HIV-negative donors. In contrast, no effect on the expression of PD-L2 or PD-1 molecules was detected. The induction of PD-L1 on MoDCs by HIV-1 Tat (i) occurred in dose- and time-dependent manners, (ii) was mediated by the N-terminal 1-45 fragment of Tat, (iii) did not require direct cell-cell contact but appeared rather to be mediated by soluble factor(s), (iv) was abrogated following neutralization of tumor necrosis factor alpha (TNF-α) or blocking of Toll-like receptor 4 (TLR4), (v) was absent in TLR4-knockoout (KO) mice but could be restored following incubation with Tat-conditioned medium from wild-type DCs, (vi) impaired the capacity of MoDCs to functionally stimulate T cells, and (vii) was not reversed functionally following PD-1/PD-L1 pathway blockade, suggesting the implication of other Tat-mediated coinhibitory pathways. Our results demonstrate that HIV-1 Tat protein upregulates PD-L1 expression on MoDCs through TNF-α- and TLR4-mediated mechanisms, functionally compromising the ability of DCs to stimulate T cells. The findings offer a novel potential molecular target for the development of an anti-HIV-1 treatment.

IMPORTANCE:

The objective of this study was to investigate the effect of human immunodeficiency virus type 1 (HIV-1) Tat on the PD-1/PD-L1 coinhibitory pathway on human monocyte-derived dendritic cells (MoDCs). We found that treatment of MoDCs from either healthy or HIV-1-infected patients with HIV-1 Tat protein stimulated the expression of PD-L1. We demonstrate that this stimulation was mediated through an indirect mechanism, involving tumor necrosis factor alpha (TNF-α) and Toll-like receptor 4 (TLR4) pathways, and resulted in compromised ability of Tat-treated MoDCs to functionally stimulate T-cell proliferation.

PMID:
24696476
PMCID:
PMC4054384
DOI:
10.1128/JVI.00825-14
[Indexed for MEDLINE]
Free PMC Article

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