Abstract
Antiretroviral therapy has dramatically improved the lives of human immunodeficiency virus 1 (HIV-1) infected individuals. Nonetheless, HIV-associated neurocognitive disorders (HAND), which range from undetectable neurocognitive impairments to severe dementia, still affect approximately 50% of the infected population, hampering their quality of life. The persistence of HAND is promoted by several factors, including longer life expectancies, the residual levels of virus in the central nervous system (CNS) and the continued presence of HIV-1 regulatory proteins such as the transactivator of transcription (Tat) in the brain. Tat is a secreted viral protein that crosses the blood–brain barrier into the CNS, where it has the ability to directly act on neurons and non-neuronal cells alike. These actions result in the release of soluble factors involved in inflammation, oxidative stress and excitotoxicity, ultimately resulting in neuronal damage. The percentage of methamphetamine (MA) abusers is high among the HIV-1-positive population compared to the general population. On the other hand, MA abuse is correlated with increased viral replication, enhanced Tat-mediated neurotoxicity and neurocognitive impairments. Although several strategies have been investigated to reduce HAND and MA use, no clinically approved treatment is currently available. Here, we review the latest findings of the effects of Tat and MA in HAND and discuss a few promising potential therapeutic developments.
Highlights
The human immunodeficiency virus 1 (HIV-1) affects 35.3 million individuals worldwide (UNAIDS)
This is confirmed in animal studies using the fully replicating virus in combination with MA, showing greater alteration of cognitive and locomotor behavior when compared with either treatment alone (Liu et al, 2009; Kass et al, 2010; reviewed in Silverstein et al, 2011; Kesby et al, 2015), an effect mediated by inflammation and oxidative stress processes (Maragos et al, 2002; Theodore et al, 2006a,b,c,d; Banerjee et al, 2010)
The biological effects of MA abuse and Tat protein have been extensively studied in the past, the result of their interaction is still not fully understood
Summary
The human immunodeficiency virus 1 (HIV-1) affects 35.3 million individuals worldwide (UNAIDS). Regardless of the means, among the consequences of HIV infection is synaptodendritic injury to neurons that closely correlates to the occurrence and severity of neurocognitive disorders (reviewed in Ellis et al, 2007) This synaptodendritic injury may be driven by viral replication in non-neuronal cells and is defined by structural and chemical changes occurring at neuronal synapses, resulting in a disturbance of communication between neurons responsible for behaviors such as memory, learning, and executive functions (reviewed in Ellis et al, 2007; reviewed in Nath and Steiner, 2014). Given that no treatment is yet available against the neurotoxic activity of Tat (Mediouni et al, 2012), or the additive detrimental effects of both Tat and MA, we will conclude with a discussion of some promising candidates emerging in the literature
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