Neuronal Stress and Injury Caused by HIV-1, cART and Drug Abuse: Converging Contributions to HAND

Abstract

Multiple mechanisms appear to contribute to neuronal stress and injury underlying HIV-associated neurocognitive disorders (HAND), which occur despite the successful introduction of combination antiretroviral therapy (cART). Evidence is accumulating that components of cART can itself be neurotoxic upon long-term exposure. In addition, abuse of psychostimulants, such as methamphetamine (METH), seems to compromise antiretroviral therapy and aggravate HAND. However, the combined effect of virus and recreational and therapeutic drugs on the brain is still incompletely understood. However, several lines of evidence suggest a shared critical role of oxidative stress, compromised neuronal energy homeostasis and autophagy in promotion and prevention of neuronal dysfunction associated with HIV-1 infection, cART and psychostimulant use. In this review, we present a synopsis of recent work related to neuronal stress and injury induced by HIV infection, antiretrovirals (ARVs) and the highly addictive psychostimulant METH.

Keywords: HAND; HIV-1; anti-retroviral; methamphetamine; neurotoxicity.

Figure 1

Treatment of HIV-1 infection with cART greatly reduces viral loads in periphery and the central nervous system (CNS), the incidence of HIV-associated dementia (HAD) and acquired immunodeficiency syndrome (AIDS)-related deaths. HIV-1 or its components, methamphetamine (METH) and some antiretrovirals used in combined antiretroviral therapy (cART) can induce oxidative and endoplasmic retriculum (ER) stress, compromise autophagy and neuronal energy homeostasis and trigger functional as well as structural neuronal injury. However, even without overt structural damage, diminished adenosine triphosphate (ATP) levels indicate that neurons may lose, at least in part, the energy reserve that is vital to maintaining their normal membrane potential and physiological functions, such as homeostatic regulation of neurotransmission. A compromised neuronal energy homeostasis may explain why cART permits the occurrence of HIV-associated mild neurocognitive disorders (MND). Interestingly, neuronal energy levels can apparently drop significantly during exposure to some drugs or combinations thereof without necessarily destructing neuronal dendrites and pre-synaptic terminals, suggesting that a restoration of full neuronal function may be possible.