Interactions of HIV and methamphetamine: Cellular and molecular mechanisms of toxicity potentiation

Abstract

Methamphetamine (METH) is a highly addictive psychostimulant drug, whose abuse has reached epidemic proportions worldwide. METH use is disproportionally represented among populations at high risks for developing HIV infection or who are already infected with the virus. Psychostimulant abuse has been reported to exacerbate the cognitive deficits and neurodegenerative abnormalities observed in HIV-positive patients. Thus, the purpose of the present paper is to review the clinical and basic observations that METH potentiates the adverse effects of HIV infection. An additional purpose is to provide a synthesis of the cellular and molecular mechanisms that might be responsible for the increased toxicity observed in co-morbid patients. The reviewed data indicate that METH and HIV proteins, including gp120, gp41, Tat, Vpr and Nef, converge on various caspase-dependent death pathways to cause neuronal apoptosis. The role of reactive microgliosis in METH- and in HIV-induced toxicity is also discussed.

Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage

“…Neuronal damage found in neuro-AIDS can have different origins, ranging from neurotoxins and viral proteins produced by HIV-infected cells in the CNS (44,(68)(69)(70)(71) to toxicity induced by the use of both therapeutic and recreational drugs (14,17,37,38,72). In this study, we assessed for the first time experimentally the contribution to neuronal injury of METH, ARVs, and an established viral neurotoxin, HIV-1 gp120, in combination.…”

“…Additionally, increased viral loads have been linked to METH use in ART-receiving HIV-positive individuals (29,36). The combination of METH and HIV-1 seems to cause more neurocognitive deficits and neuropathology than either agent alone, but the potential mechanistic interactions of virus, antiviral treatment, and the psychostimulant drug is largely unknown (22,35,37). Abuse of METH seems to increase neuronal release of monoamine neurotransmitters, particularly dopamine (DA), in the synapse, which can be toxic to nerve terminals (38,39).…”

Antiretroviral Therapy and HIV-Associated Neurocognitive Disorders

“…As mentioned in previous sections, BBB dysfunction and neurotoxicity are observed during the course of HIV infection as well as in response to ARV exposure and include similar mechanisms. Considering that the prevalence of HIV infection is 12-17% among illicit drug users (Cadet and Krasnova 2007), animal and clinical studies are essential to tailor cART regimens that reach sufficient CSF concentrations and yet do not augment neurotoxicity that might already be occuring in response to drug abuse.…”

D1/NMDA Receptors and Concurrent Methamphetamine+HIV-1 Tat Neurotoxicity

“…Clinical studies indicate that HIV-1 infection (Grant 2008) and METH dependence (Gouzoulis-Mayfrank and Daumann 2009; Scott et al 2007) are associated with neuropsychological deficits, suggesting that these factors in combination may produce additive or even synergistic adverse effects on neural function (Langford et al 2003). While potential mechanisms of adverse independent effects of METH abuse or HIV-1 infection on neuronal functioning have been the subject of many experimental reports (Cadet and Krasnova 2007; Cadet and Krasnova 2009), fewer studies have been reported on the combined effects of METH and HIV-1 in the brain (Ferris et al 2008; Rippeth et al 2004). This cooperation between HIV-1 and METH may reflect common pathways to neural injury involving both cytotoxic and apoptotic mechanisms (Purohit et al 2011).…”