The cross-talk of HIV-1 Tat and methamphetamine in HIV-associated neurocognitive disorders

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.

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

“…Regarding the interactions of Tat and Meth, our findings were surprising. As mentioned, our previous work has shown that these Meth sensitized animals experience an important repression in the dopaminergic system that is further enhanced by Tat [43], resulting in higher locomotor responses to the drug challenge and replicating aspects of the pathology found in HIV-infected humans [43,109,110]. In chronic and binge Meth administration regimens performed in the same mouse model, the induction of Tat expression during the final cycle of Meth exposure did not impact brain reward function during withdrawal.…”

Lifetime methamphetamine dependence is associated with cerebral microgliosis in HIV-1-infected adults

“…The presence of cerebral microgliosis in association with lifetime Meth dependence in HIV-infected individuals suggests that Meth alone or interactions between Meth and HIV (such as HIV-1 Tat and gp120 proteins) induce long-lasting microglial activation (Kuhn et al 2011; Mediouni et al 2015). It is also possible that microglial activation occurs in response to chronic Meth-induced neuronal injury (Bowyer et al 2008).…”

Effects of HIV and Methamphetamine on Brain and Behavior: Evidence from Human Studies and Animal Models

“…The toxic effects of either Meth or Tat or both on the blood-brain barrier, neurons, and glial cells have been investigated extensively in in vitro cell systems (Cisneros and Ghorpade 2012; Borgmann and Ghorpade 2015; Mediouni et al 2015). Both Meth and Tat inhibited astroglial Wnt/β-catenin signaling (Sharma et al 2011; Henderson et al 2012).…”