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PLoS One. 2017 Nov 1;12(11):e0186823. doi: 10.1371/journal.pone.0186823. eCollection 2017.

IL-23 signaling in Th17 cells is inhibited by HIV infection and is not restored by HAART: Implications for persistent immune activation.

Author information

1
The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
2
Department of Biochemistry, Microbiology, and Immunology, The University of Ottawa, Ottawa, Ontario, Canada.
3
The Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
4
Division of Infectious Diseases, The Ottawa Hospital, Ottawa, Ontario, Canada.

Abstract

OBJECTIVES:

HIV infection causes a profound depletion of gut derived Th17 cells, contributing to loss of mucosal barrier function and an increase in microbial translocation, thus driving systemic immune activation. Despite normalization of circulating CD4+ T cell counts with highly active antiretroviral therapy (HAART), Th17 frequency and function often remain impaired. Given the importance of interleukin (IL)-23 in the generation and stabilization of Th17 cells we hypothesized that impaired IL-23 signaling causes persistent Th17 dysfunction in HIV infection.

METHODS:

The effects of in vitro HIV infection on responses to IL-23 in Th17 cells were examined. These included the production of IL-17, phosphorylated STAT3 (pSTAT3) and the transcription of retinoic acid orphan receptor C (RORC) gene. Blood derived Th17 cells from untreated and HAART-treated HIV-infected individuals were also examined for the IL-23 induced production of phosphorylated STAT3 (pSTAT3) and the expression of the IL-23 receptors.

RESULTS:

In vitro HIV infection significantly inhibited IL-17 production and IL-23 induced pSTAT3 while expression of RORC RNA was unaffected. Th17 cells isolated from untreated and HAART-treated HIV-infected individuals showed complete loss of IL-23 induced pSTAT3 without a decrease in the expression of the IL-23 receptors.

CONCLUSIONS:

This study is the first to demonstrate an effect of HIV on the IL-23 signaling pathway in Th17 cells. We show that in vitro and in vivo HIV infection results in impaired IL-23 signaling which is not reversed by HAART nor is it a result of reduced receptor expression, suggesting that HIV interferes with IL-23-activated signaling pathways. These findings may explain the inability of HAART to restore Th17 frequency and function and the resulting persistent chronic immune activation observed in HIV infected individuals.

PMID:
29091911
PMCID:
PMC5665519
DOI:
10.1371/journal.pone.0186823
[Indexed for MEDLINE]
Free PMC Article

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