Drug abuse and HIV/AIDS are interlinked epidemics because of increased spread of HIV-1 through needle sharing and through the exchange of sex for drugs. During the past decade, we have proposed that, besides peripheral immune dysregulation, opiates exacerbate the pathological effects of HIV in the CNS though direct actions on ?-opioid receptor expressing (MOR) neurons and glia. The CNS may be preferentially vulnerable to opiate and HIV-1 interactions because of the complexity and interrelatedness of MOR action in neurons, astroglia, microglia and endothelium. We recently reported that convergent, neurotoxic effects of Tat or gp120 and morphine are largely due to actions of MOR+ glia. Our in vivo work supports a central role for glia in sublethal/lethal synaptodendritic injury. Morphine worsens structural and functional irregularities in hippocampus and striatum of Tat-expressing mice, including spine losses and synaptodendritic injury. Neurotoxic interactions with morphine and gp120 are HIV strain specific. Medium from monocytes exposed to live or UV-inactivated R5-tropic HIV-1SF162 virions is toxic to neurons;this is significantly attenuated by the CCR5 antagonist maraviroc. We hypothesize that opiate-induced exacerbation of HIV toxicity is regulated through differential CCR5 signaling between microglia, astroglia, and neurons, which can injure or protect neurons depending on context. We propose that opiates and Tat or HIV interact downstream of TNF? to enhance inflammatory chemokine release from astroglia. In particular, convergent effects of opiates and Tat/HIV appear to dysregulate CCL5/CCR5 signaling, creating a milieu that promotes microglial motility and spiraling microglial activation. Our hypotheses are tested in 3 aims that examine individual roles of astroglia and microglia in driving neurotoxic opiate-HIV interactions.
Aims 1 &2 use murine models for both: a) long-term, repeated imaging of cell death and sublethal neurodegenerative changes;and b) in vivo studies to detect population changes, neuron pathology, and behavioral deficits. Models include mice with cell-specific Cre-lox ablation of MOR, and inducible Tat transgenic mice crossed with CCL5-/- or CCR-/- mice.
In Aim 3, human glia and neurons are used to study neurodegenerative changes due to HIV and opiate effects related to CCL5- CCR5 signaling in an infectious model with multiple strains of HIV. Infectious/non-infectious effects of CCR5 activation are sorted using live and inactivated virus, and mutant viral strains. The CCR5 pathway is especially relevant to HIV. CCR5 is an HIV co-receptor for M-tropic strains;CCR5 polymorphisms affect disease susceptibility;the CCR5 antagonist maraviroc slows HIV progression clinically. Studies are essential for informing therapeutic strategies. By defining how each glial type contributes to CCL5/CCR5 dysregulation, judicious cell- and pathway-specific measures to prevent the neurotoxic sequelae of opiate-HIV co-exposure can be designed.
HIV infection and injection drug use are interlinked epidemics with devastating consequences for public health. Opioid drug abuse appears to enhance CNS deficits that occur due to HIV-1 infection. Our previous work showed that glia are critical mediators of combined neurotoxic effects of opiates and HIV proteins. This project examines the respective roles of astroglia and microglia in orchestrating synergistic neurotoxicity. We propose that CCL5-CCR5 signaling is disrupted by opiate-HIV interactions in complex systems. Upregulation of CCL5 release from astroglia, and enhanced activation of microglia via CCR5, drives a cascade of events that enhances synaptodendritic injury, and that may be reversible. Identifying the cellular source of opiate-HIV synergy and the key intercellular signals will be a critical step towards interrupting neurotoxic events.
|Dever, Seth M; Costin, Blair N; Xu, Ruqiang et al. (2014) Differential expression of the alternatively spliced OPRM1 isoform ?-opioid receptor-1K in HIV-infected individuals. AIDS 28:19-30|
|El-Hage, Nazira; Rodriguez, Myosotys; Podhaizer, Elizabeth M et al. (2014) Ibudilast (AV411), and its AV1013 analog, reduce HIV-1 replication and neuronal death induced by HIV-1 and morphine. AIDS 28:1409-19|
|Masvekar, Ruturaj R; El-Hage, Nazira; Hauser, Kurt F et al. (2014) Morphine enhances HIV-1SF162-mediated neuron death and delays recovery of injured neurites. PLoS One 9:e100196|
|El-Hage, Nazira; Dever, Seth M; Podhaizer, Elizabeth M et al. (2013) A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-*-opioid receptor interactions between human astroglia and microglia. AIDS 27:2181-90|