Nucleoside reverse transcriptase inhibitors (NRTIs) induce proinflammatory cytokines in the CNS via Wnt5a signaling

Ting Wu, Juan Zhang, Mingxing Geng, Shao-Jun Tang, Wenping Zhang, Jianhong Shu

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

HAART is very effective in suppressing HIV-1 replication in patients. However, patients staying on long-term HAART still develop various HIV-associated neurological disorders, even when the viral load is low. The underlying pathogenic mechanisms are largely unknown. Emerging evidence implicated that persistent neuroinflammation plays an important role in NeuroAIDS. Although residual virus or viral proteins are commonly thought as the causal factors, we are interested in the alternative possibility that HAART critically contributes to the neuroinflammation in the central nervous system (CNS). To test this hypothesis, we have determined the effect of NRTIs on the expression of proinflammatory cytokines in the various CNS regions. Mice (C57Bl/6) were administered with AZT (Zidovudine 100 mg/kg/day), 3TC (Lamivudine 50 mg/kg/day) or D4T (Stavudine 10 mg/kg/day) for 5 days, and cortices, hippocampi and spinal cords were collected for immunoblotting. Our results showed that NRTI administration up-regulated cytokines, including IL-1β, TNF-α and IL-6 in various CNS regions. In addition, we found that NRTIs also up-regulated Wnt5a protein. Importantly, BOX5 attenuated NRTI-induced cytokine up-regulation. These results together suggest that NRTIs up-regulate proinflammatory cytokines via a Wnt5a signaling-dependent mechanism. Our findings may help understand the potential pathogenic mechanisms of HAART-associated NeuroAIDS and design effective adjuvants.

Original languageEnglish (US)
Article number4117
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Reverse Transcriptase Inhibitors
Nucleosides
Highly Active Antiretroviral Therapy
Central Nervous System
Cytokines
Stavudine
Lamivudine
Up-Regulation
Zidovudine
Viral Proteins
Nervous System Diseases
Viral Load
Interleukin-1
Immunoblotting
HIV-1
Interleukin-6
Hippocampus
Spinal Cord
HIV
Viruses

ASJC Scopus subject areas

  • General

Cite this

Nucleoside reverse transcriptase inhibitors (NRTIs) induce proinflammatory cytokines in the CNS via Wnt5a signaling. / Wu, Ting; Zhang, Juan; Geng, Mingxing; Tang, Shao-Jun; Zhang, Wenping; Shu, Jianhong.

In: Scientific Reports, Vol. 7, No. 1, 4117, 01.12.2017.

Research output: Contribution to journalArticle

Wu, Ting ; Zhang, Juan ; Geng, Mingxing ; Tang, Shao-Jun ; Zhang, Wenping ; Shu, Jianhong. / Nucleoside reverse transcriptase inhibitors (NRTIs) induce proinflammatory cytokines in the CNS via Wnt5a signaling. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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abstract = "HAART is very effective in suppressing HIV-1 replication in patients. However, patients staying on long-term HAART still develop various HIV-associated neurological disorders, even when the viral load is low. The underlying pathogenic mechanisms are largely unknown. Emerging evidence implicated that persistent neuroinflammation plays an important role in NeuroAIDS. Although residual virus or viral proteins are commonly thought as the causal factors, we are interested in the alternative possibility that HAART critically contributes to the neuroinflammation in the central nervous system (CNS). To test this hypothesis, we have determined the effect of NRTIs on the expression of proinflammatory cytokines in the various CNS regions. Mice (C57Bl/6) were administered with AZT (Zidovudine 100 mg/kg/day), 3TC (Lamivudine 50 mg/kg/day) or D4T (Stavudine 10 mg/kg/day) for 5 days, and cortices, hippocampi and spinal cords were collected for immunoblotting. Our results showed that NRTI administration up-regulated cytokines, including IL-1β, TNF-α and IL-6 in various CNS regions. In addition, we found that NRTIs also up-regulated Wnt5a protein. Importantly, BOX5 attenuated NRTI-induced cytokine up-regulation. These results together suggest that NRTIs up-regulate proinflammatory cytokines via a Wnt5a signaling-dependent mechanism. Our findings may help understand the potential pathogenic mechanisms of HAART-associated NeuroAIDS and design effective adjuvants.",
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