Morphine counteracts the antiviral effect of antiretroviral drugs and causes upregulation of p62/SQSTM1 and histone-modifying enzymes in HIV-infected astrocytes
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Accelerated neurological disorders are increasingly prominent among the HIV-infected population and are likely driven by the toxicity from long-term use of antiretroviral drugs. We explored potential side effects of antiretroviral drugs in HIV-infected primary human astrocytes and whether opioid co-exposure exacerbates the response. HIV-infected human astrocytes were exposed to the reverse transcriptase inhibitor, emtricitabine, alone or in combination with two protease inhibitors ritonavir and atazanavir (ERA) with and without morphine co-exposure. The effect of the protease inhibitor, lopinavir, alone or in combination with the protease inhibitor, abacavir, and the integrase inhibitor, raltegravir (LAR), with and without morphine co-exposure was also explored. Exposure with emtricitabine alone or ERA in HIV-infected astrocytes caused a significant decrease in viral replication and attenuated HIV-induced inflammatory molecules, while co-exposure with morphine negated the inhibitory effects of ERA, leading to increased viral replication and inflammatory molecules. Exposure with emtricitabine alone or in combination with morphine caused a significant disruption of mitochondrial membrane integrity. Genetic analysis revealed a significant increase in the expression of p62/SQSTM1 which correlated with an increase in the histone-modifying enzyme, ESCO2, after exposure with ERA alone or in combination with morphine. Furthermore, several histone-modifying enzymes such as CIITA, PRMT8, and HDAC10 were also increased with LAR exposure alone or in combination with morphine. Accumulation of p62/SQSTM1 is indicative of dysfunctional lysosomal fusion. Together with the loss of mitochondrial integrity and epigenetic changes, these effects may lead to enhanced viral titer and inflammatory molecules contributing to the neuropathology associated with HIV.
KeywordsAntiretroviral drugs Opioid Autophagy Scaffold protein Arginine methyl transferase
We gratefully acknowledge the support of the National Institutes of Health (NIH)-National Institute on Drug Abuse (NIDA) grants R01 DA036154; R01 DA036154-S1 (Diversity Supplement in support to J.L); R21 DA041287 to N.E.H. We also acknowledge the financial support of Presidential Fellowship provided to C.R.O. by University Graduate School, Florida International University.
M.R. performed and analyzed the experiments shown in Figs. 1, 2, 3, 4, and 5 and Supplementary Figs. S1–S2 and wrote the manuscript. J.L. performed and analyzed the experiments shown in Fig. 4a–b, 5a, and Supplementary Fig. 2b and assisted in editing of the manuscript. C.R.O. provided assistance regarding the experiment shown in Fig. 3 and assisted in writing the “Introduction” and “Method” sections. S.P. provided assistance regarding the experiment shown in Fig. 4b. M.K. provided assistance regarding the experiment shown in Supplementary Fig. 2b. F.K. provided technical expertise and assisted in the editing of the manuscript. N.E.-H. designed, conceived, analyzed, and coordinated the study and wrote the manuscript. All authors reviewed the results and approved the final version of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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