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

Abstract

Human immunodeficiency virus (HIV)-infected individualswho abuse opiates show faster progression to AIDS, and enhanced incidence of HIV-1 encephalitis. Most opiates with abuse liability are preferential agonists for l-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 1/2 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 1/2 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 1/2 morphine suggest that toxicity toward OLs may be accompanied by heightened OL turnover. V V C

Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

“…South Carolina) has been detailed previously. 10,14 A tetracycline (tet) "on" system was used for generation of inducible constructs. HIV-1 Tat 1-86 (IIIB) was cloned downstream of a tet-responsive element (TRE) in the pTREX vector (Clonetech, Mountain View, CA).…”

“…In combination, morphine exposure and Tat induction cause severe deficits in spine numbers and defects in dendritic morphology (R-Y), including severe beading and degeneration (W), qualitatively worse than with either treatment alone. Different z-plane images of some neurons were projected into a single 2-dimensional image using deconvolution (AutoQuant) (C-H, T-U, X-Y) or extended focusing (Extended Focus Module, AxioVision, Zeiss) (A, B, K, M, R) software as described before 10 ; scale bars ϭ 20 m (A) and 10 m (B, C, J, K, M); (B, E, F, I), (C-D, G-H, N, O, Q, T, U, W-Y), (K, L) and (M, P, R, S, V) are the same magnification.…”

“…3 induction of Tat by DOX in these transgenic mice using PCR amplification from specific Tat primers. 10,14,38 In the present study, we screened multiple anti-Tat antibodies for their ability to detect Tat by immunostaining and western blot. Although not all antibodies detected Tat, consistent fluorescent immunolabeling in Tat(ϩ) DOX mice was obtained using Tat ab24778 (Abcam) (Figure 1).…”

“…[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][8][9][10][11][12][13][14][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.…”

“…24 -26 The present work was undertaken to extend previous results suggesting that HIV-1 Tat exposure might disrupt endogenous opioid and chemokine signaling. 10,24,27 Addi-tionally, we tested for subtle neuropathological changes that might be caused by HIV-1 Tat and opiate interactions since neuron death (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) was not observed in our previous study. 14 Wild-type and transgenic mice expressing HIV-1 Tat 1-86 regulated by a doxycycline (DOX) inducible, glial fibrillary acidic protein (GFAP) promoter were continuously treated with placebo, morphine, and/or naltrexone (s.c. implants) Ϯ DOX for 2, 7, or 10 days.…”