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The effects of MAPK p38α on AZT resistance against reactivating HIV-1 replication in ACH2 cells

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Abstract

Antiretroviral therapy (ART) has remarkably decreased HIV-related mortality. However, drug-resistant HIV variants pose a potential threat to the long-term success of ART. Both HIV mutants and host factors can cause HIV drug resistance. Using susceptible ACH2 cells chronically infected with HIV-1, we examined the effects of MAPK p38α on AZT resistance against reactivating HIV-1 replication that can be activated by HIV-1 superinfection. We found that HIV-1 superinfection induced more viral production, which was diminished by p38 inhibitor, SB203580, and by AZT in cells infected with non-AZT-resistant HIV-1 strain MN. p38α expression can resist action of AZT in inhibition of HIV-1 replication with increased expression of transcription factor, NF-ĸBp65, SP1, and c-Fos through activation of TCR-related pathways with upregulation of CD3, TCRα, TCRβ, Zap-70, PKC, PLCγ1, GRB2, and PI3K/Akt expression. In HIV-1 MN superinfection under AZT treatment, expression of p38α led to HIV vif expression and inhibited APOBEC3G expression. We also investigated effects of p38α on gp130/JAK-STAT pathways, in which p38α increased expression of protein, gp130, EGFR, Jak2, STAT1, STAT3, STAT5, ras, and TF. p38α could induce apoptotic pathways with upregulation of Fas, FADD, Caspase-8, p53, and Bax, and downregulation of Bcl2 expression. These results indicate that p38α plays a positive role in reactivation of viral replication from HIV-1 latent infection and leads to HIV-1 AZT resistance. In conclusion, MAPKp38α can activate HIV-1 replication inhibited by AZT from HIV-1 latent infection and may be used as a latency reversal agent. The activation involves induction of several cell signaling pathways that are required for HIV-1 replication, which may be integrated into future viral remission strategies.

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Acknowledgements

The authors wish to thank Dr. Krishnakumar Devadas and Dr. Mohan Setty for critical review of this manuscript. We further acknowledge the NIH AIDS reagent repository for the reagents. This work was supported by an internal CBER grant. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.

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Authors and Affiliations

  1. Lab of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA

    Xue Wang, Jiangqin Zhao, Viswanath Ragupathy & Indira Hewlett

  2. Lab of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Building 72, Rm 4322, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA

    Xue Wang & Indira Hewlett

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  1. Xue Wang
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  2. Jiangqin Zhao
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  4. Indira Hewlett
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Contributions

XW and IH conceived and designed the experiments; XW, JZ, and VR performed the experiments; XW analyzed the data; and XW and IH wrote the paper. All authors have read and approved the final manuscript.

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Correspondence to Xue Wang or Indira Hewlett.

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Wang, X., Zhao, J., Ragupathy, V. et al. The effects of MAPK p38α on AZT resistance against reactivating HIV-1 replication in ACH2 cells. Mol Cell Biochem 462, 41–50 (2019). https://doi.org/10.1007/s11010-019-03608-6

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  • DOI: https://doi.org/10.1007/s11010-019-03608-6

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