Morphine counteracts the antiviral effect of antiretroviral drugs and causes upregulation of p62/SQSTM1 and histone-modifying enzymes in HIV-infected astrocytes

As HIV-infected individuals live longer due to effective antiretroviral therapy (cART), neurological complications remain a significant concern. Many patients also use opioids for chronic pain management, creating potential, understudied drug-drug interactions. This study investigated how morphine influences the antiviral efficacy and cellular toxicity of two common cART regimens in HIV-infected human astrocytes, which serve as a viral reservoir in the brain.

The researchers treated HIV-infected primary human astrocytes with two drug combinations: emtricitabine plus ritonavir and atazanavir (ERA) or lopinavir plus abacavir and raltegravir (LAR). These were tested both with and without 500 nM morphine co-exposure over 3, 5, and 7 days. The team assessed viral replication, inflammatory cytokine and chemokine secretion (IL-6, TNF-alpha, MCP-1, RANTES), mitochondrial integrity, and the expression of stress-related markers such as p62/SQSTM1 and various histone-modifying enzymes.

The researchers found that morphine dramatically alters the effectiveness of cART. While the ERA regimen successfully reduced HIV replication and inflammation, co-exposure with morphine completely negated these benefits, causing a spike in viral titer and pro-inflammatory signaling. In contrast, the LAR regimen maintained its inhibitory effects even when combined with morphine.

Genetic analysis revealed that ERA, especially when combined with morphine, induced significant accumulation of the scaffold protein p62/SQSTM1, a hallmark of dysfunctional autophagosome-lysosome fusion. This suggests that the combination of drugs and opioids triggers a breakdown in the cell's ability to clear viral components through autophagy, thereby promoting viral persistence and neurotoxic inflammation. Furthermore, while the LAR regimen did not induce this p62/SQSTM1 accumulation, it did significantly increase the expression of several histone-modifying enzymes, which may contribute to a different mechanism of viral suppression.