Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

Abstract

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 and , but not ␦, 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 un- Exposure to HIV results in neurodegenerative alterations in the central nervous system (CNS) of a substantial proportion of patients, even in the era of highly active anti-retroviral therapy. Highly active anti-retroviral therapy does not readily cross the blood-brain barrier, making the CNS a safe-haven for infection, and permitting ongoing degenerative changes even when viral titers are quite low in the periphery. [1][2][3][4][5][6] There is considerable evidence, both in patients and in experimental models, that coexposure to abused opiate drugs can hasten the onset and worsen the outcome of HIV encephalitis and other neurodegenerative changes.7-15 A more limited number of studies show that opioids increase viral loads, and hasten disease progression and/or neuropathology in simian immunodeficiency models, 16 -19 although this has been controversial. 20 -22 Our in vitro work has consistently shown evidence for interactions between Tat or gp120 and morphine that accelerate neurodegeneration. These interactive effects appear to be orchestrated by glial cells, 23 and likely involve synergistic upregulation of proinflammatory chemokine/cytokine release and production of reactive species. 24 -26 The present work was undertaken to extend previous results suggesting that HIV-1 Tat exposure might disrupt endogenous opioid and chemokine signaling.

Anxiety-like behavior of mice produced by conditional central expression of the HIV-1 regulatory protein, Tat

“…However, the 19 kDa band co-varies with expected Tat expression. The discrepancy in molecular weight may be attributed to post-translational modification of Tat and is consistent with other weights so reported (Carey et al 2012; Fitting et al 2010; Park et al 2000). Despite the need for better antibodies to Tat, the expression of this protein in the GT-tg mouse (Kim et al 2003) is generally consistent with unbound concentrations observed in HIV-positive sera (Westendorp et al 1995; Xiao et al 2000).…”

“…Furthermore, expression of Tat 1-86 protein was transient, as antibody labeling declined one week after induction and did not differ from control levels two weeks after induction. Despite the known difficulties in conducting protein analyses of in vivo Tat expression, we and others have previously demonstrated similar effects (Carey et al 2012; Fitting et al 2010; Kim et al 2003). Many of the available Tat antibodies generate nonspecific labeling at the predicted weights of Tat protein (14 kDa; Fitting et al 2010 and Carey et al 2012, supplemental material), and indeed nonspecific labeling at 14 kDa was again detected herein, even among control C57BL/6J brain samples that lack Tat protein.…”

“…Despite the known difficulties in conducting protein analyses of in vivo Tat expression, we and others have previously demonstrated similar effects (Carey et al 2012; Fitting et al 2010; Kim et al 2003). Many of the available Tat antibodies generate nonspecific labeling at the predicted weights of Tat protein (14 kDa; Fitting et al 2010 and Carey et al 2012, supplemental material), and indeed nonspecific labeling at 14 kDa was again detected herein, even among control C57BL/6J brain samples that lack Tat protein. The limitations of available detection tools are notable, as Tat protein is typically expressed on arbitrary scales, even in clinical tissues (Wesselingh et al 1993).…”

“…We and others have previously demonstrated the Tat 1-86 protein is expressed in a doxycycline-dependent manner, selectively in the brain of GT-tg bigenic mice (Carey et al 2012; Kim et al 2003) and another conditional expression mouse model (Fitting et al, 2010). Expression of Tat protein in the GT-tg bigenic mouse model emulates clinical findings of HIV characterized by central macrophage/monocyte infiltration and neuronal cell death (Kim et al 2003), cognitive impairment (Carey et al 2012), reductions in limbic gray matter volume (Carey et al 2013), and increases in psychostimulant reward (Paris et al 2013).…”

HIV-1 Proteins, Tat and gp120, Target the Developing Dopamine System

“…Moreover, Tat protein-induced synaptodendritic damage occurs prior to cell death, at very low Tat concentrations, and may be reversible [220]. Synaptic alterations in pyramidal cells of the hippocampus [221], as well as decreased spine density in medium spiny neurons [222], have also been reported in mice conditionally expressing the HIV-1 Tat protein in astrocytes. Similarly, we have recently reported that HIV-1 Tg rats have altered dendritic spines in the nucleus accumbens medium spiny neurons [159].…”