| HIV progression and HIV-associated neurocognitive disorders (HAND) are directly and indirectly exacerbated by substances of abuse, including opiates. The mechanisms by which opiates aggravate HIV and HAND are complex and not well defined. One critical factor in the neuropathogenesis of HIV relates to the interaction between opioid receptors and the HIV co-receptor, CXCR4, which is abundantly expressed in both the immune and nervous system. Importantly, CXCR4 and its natural ligand (the chemokine CXCL12/SDF-1) are involved in fundamental neuronal and glia functions, including neurotransmission, cell differentiation, and survival. Our previous studies in murine models have shown that prolonged morphine treatment down-regulates CXCR4 function due to increased levels of a novel regulator of CXCR4, the ubiquitous iron binding protein Ferritin Heavy Chain (FHC), and that this protein mediates the effect of morphine on CXCR4 both in vitro and in vivo. These data suggest that alterations of CXCR4 function induced by opiates may contribute to HIV ieuropathology, via regulation of FHC. To further test this hypothesis and evaluate potential clinical implications, we measured protein expression of FHC, CXCR4 and pCXCR4 (Ser339 - as indication of receptor status) within brain tissue samples from control subjects, illicit drug abusers (including opiate users), and HIV+ patients by multispectral immunohistological image analysis. Our results demonstrate elevated FHC protein and decreased pCXCR4 expression within digitally isolated cortical neurons of patients with a history of drug use or HIV. Additionally, we studied non-human primates (NHPs) treated with morphine, SIV or both. Importantly, we found consistent results between the human and NHP cohorts suggesting that opiates or HIV/SIV alone are sufficient to induce neuronal FHC expression in vivo and that this is associated with disruption of CXCL12/CXCR4 signaling. Furthermore, preliminary analyses on both human and NHP cohorts suggest neuronal FHC expression is associated with disease progression and neurocognitive impairment. |
