Interactive comorbidity between opioid drug abuse and HIV-1 Tat: chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons.

HIV-1 infection predisposes the central nervous system to damage by opportunistic infections and environmental insults. Such maladaptive plasticity may underlie the exaggerated comorbidity seen with HIV-1 infection and opioid abuse. Although morphine and HIV-1 Tat synergize at high concentrations to increase neuronal death in vitro, we questioned whether chronic low Tat exposure in vivo might contribute to the spectrum of neuropathology through sublethal neuronal injury. We used a doxycycline-driven, inducible, HIV-1 Tat transgenic mouse, in which striatal neuron death was previously shown to be absent, to examine effects of differential Tat expression, alone and combined with morphine. Low constitutive Tat expression caused neurodegeneration; higher levels induced by 7 days of doxycycline significantly reduced dendritic spine numbers. Moreover, Tat expression widely disrupted the endogenous opioid system, altering mu and kappa, but not delta, opioid receptor and proopiomelanocortin, proenkephalin, and prodynorphin transcript levels in cortex, hippocampus, and striatum. In addition to markedly reducing spine density by itself, morphine amplified the effect of higher levels of Tat on spines, and also potentiated Tat-mediated dendritic pathology, thus contributing to maladaptive neuroplasticity at multiple levels. The dendritic pathology and reductions in spine density suggest that sustained Tat +/- morphine exposure underlie key aspects of chronic neurodegenerative changes in neuroAIDS, which may contribute to the exacerbated neurological impairment in HIV patients who abuse opioids.

HIV-1 Tat and morphine have interactive effects on oligodendrocyte survival and morphology.

Human immunodeficiency virus (HIV)-infected individuals who abuse opiates show faster progression to AIDS, and enhanced incidence of HIV-1 encephalitis. Most opiates with abuse liability are preferential agonists for mu-opioid receptors (MORs), and MORs are expressed on both neurons and glia, including oligodendrocytes (OLs). Tat, gp120, and other viral toxins, cause neurotoxicity in vitro and/or when injected into brain, and co-exposure to opiates can augment HIV-1 protein-induced insults to both glial and neuronal populations. We examined the effects of HIV-1 Tat +/- opiate exposure on OL survival and differentiation. In vivo studies utilized transgenic mice expressing Tat(1-86) regulated by an inducible glial fibrillary acidic protein promoter. Although MBP levels were unchanged on immunoblots, certain structural and apoptotic indices were abnormal. After only 2 days of Tat induction, OLs showed an upregulation of active caspase-3 that was enhanced by morphine exposure. Tat also upregulated TUNEL staining, but only in the presence of morphine. Tat significantly reduced the length of processes in Golgi-Kopsch impregnated OLs. A greater proportion of cells exhibited diminished or aberrant cytoplasmic processes, especially when mice expressing Tat were co-exposed to morphine. Collectively, our data show that OLs in situ are extremely sensitive to effects of Tat +/- morphine, although it is not clear if immature OLs as well as differentiated OLs are targeted equally. Significant elevations in caspase-3 activity and TUNEL labeling, and evidence of increased degeneration/regeneration of OLs exposed to Tat +/- morphine suggest that toxicity toward OLs may be accompanied by heightened OL turnover.