HIV-associated neurocognitive disorders (HAND) persist despite the successful introduction of combination antiretroviral therapy (cART). While insufficient concentration of certain antiretrovirals (ARV) may lead to incomplete viral suppression in the brain, many ARVs are found to cause neuropsychiatric adverse effects, indicating their penetration into the central nervous system (CNS). Several lines of evidence suggest shared critical roles of oxidative and endoplasmic reticulum stress, compromised neuronal energy homeostasis, and autophagy in the promotion of neuronal dysfunction associated with both HIV-1 infection and long-term cART or ARV use. As the lifespans of HIV patients are increased, unique challenges have surfaced. Longer lives convey prolonged exposure of the CNS to viral toxins, neurotoxic ARVs, polypharmacy with prescribed or illicit drug use, and age-related diseases. All of these factors can contribute to increased risks for the development of neuropsychiatric conditions and cognitive impairment, which can significantly impact patient well-being, cART adherence, and overall health outcome. Strategies to increase the penetration of cART into the brain to lower viral toxicity may detrimentally increase ARV neurotoxicity and neuropsychiatric adverse effects. As clinicians attempt to control peripheral viremia in an aging population of HIV-infected patients, they must navigate an increasingly complex myriad of comorbidities, pharmacogenetics, drug-drug interactions, and psychiatric and cognitive dysfunction. Here we review in comparison to the neuropathological effects of HIV-1 the available information on neuropsychiatric adverse effects and neurotoxicity of clinically used ARV and cART. It appears altogether that future cART aiming at controlling HIV-1 in the CNS and preventing HAND will require an intricate balancing act of suppressing viral replication while minimizing neurotoxicity, impairment of neurocognition, and neuropsychiatric adverse effects. Schematic summary of the effects exerted on the brain and neurocognitive function by HIV-1 infection, comorbidities, psychostimulatory, illicit drugs, therapeutic drugs, such as antiretrovirals, the resulting polypharmacy and aging, as well as the potential interactions of all these factors

Viral infections remain a global public health concern and cause a severe societal and economic burden. At the organismal level, the innate immune system is essential for the detection of viruses and constitutes the first line of defense. Viral components are sensed by host pattern recognition receptors (PRRs). PRRs can be further classified based on their localization into Toll-like receptors (TLRs), C-type lectin receptors (CLR), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors (NLRs) and cytosolic DNA sensors (CDS). TLR and RLR signaling results in production of type I interferons (IFNα and -β) and pro-inflammatory cytokines in a cell-specific manner, whereas NLR signaling leads to the production of interleukin-1 family proteins. On the other hand, CLRs are capable of sensing glycans present in viral pathogens, which can induce phagocytic, endocytic, antimicrobial, and pro- inflammatory responses. Peripheral immune sensing of viruses and the ensuing cytokine response can significantly affect the central nervous system (CNS). But viruses can also directly enter the CNS via a multitude of routes, such as the nasal epithelium, along nerve fibers connecting to the periphery and as cargo of infiltrating infected cells passing through the blood brain barrier, triggering innate immune sensing and cytokine responses directly in the CNS. Here, we review mechanisms of viral immune sensing and currently recognized consequences for the CNS of innate immune responses to viruses.

HIV-1 infection frequently causes HIV-associated neurocognitive disorders (HAND) despite combination antiretroviral therapy (cART). Evidence is accumulating that components of cART can themselves be neurotoxic upon long-term exposure. In addition, abuse of psychostimulants, such as methamphetamine, seems to aggravate HAND and compromise antiretroviral therapy. However, the combined effect of virus and recreational and therapeutic drugs on the brain is poorly understood. Therefore, we exposed mixed neuronal-glial cerebrocortical cells to antiretrovirals (ARVs) (zidovudine [AZT], nevirapine [NVP], saquinavir [SQV], and 118-D-24) of four different pharmacological categories and to methamphetamine and, in some experiments, the HIV-1 gp120 protein for 24 h and 7 days. Subsequently, we assessed neuronal injury by fluorescence microscopy, using specific markers for neuronal dendrites and presynaptic terminals. We also analyzed the disturbance of neuronal ATP levels and assessed the involvement of autophagy by using immunofluorescence and Western blotting. ARVs caused alterations of neurites and presynaptic terminals primarily during the 7-day incubation and depending on the specific compounds and their combinations with and without methamphetamine. Similarly, the loss of neuronal ATP was context specific for each of the drugs or combinations thereof, with and without methamphetamine or viral gp120. Loss of ATP was associated with activation of AMP-activated protein kinase (AMPK) and autophagy, which, however, failed to restore normal levels of neuronal ATP. In contrast, boosting autophagy with rapamycin prevented the long-term drop of ATP during exposure to cART in combination with methamphetamine or gp120. Our findings indicate that the overall positive effect of cART on HIV infection is accompanied by detectable neurotoxicity, which in turn may be aggravated by methamphetamine.

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.

Infection with human immunodeficiency virus-1 (HIV-1) causes brain injury. Type I interferons (IFNα/β) are critical mediators of any anti-viral immune response and IFNβ has been implicated in the temporary control of lentiviral infection in the brain. Here we show that transgenic mice expressing HIV-1 envelope glycoprotein 120 in their central nervous system (HIVgp120tg) mount a transient IFNβ response and provide evidence that IFNβ confers neuronal protection against HIVgp120 toxicity. In cerebrocortical cell cultures, neuroprotection by IFNβ against gp120 toxicity is dependent on IFNα receptor 1 (IFNAR1) and the β-chemokine CCL4, as IFNAR1 deficiency and neutralizing antibodies against CCL4, respectively, abolish the neuroprotective effects. We findin vivothat IFNβ mRNA is significantly increased in HIVgp120tg brains at 1.5, but not 3 or 6 months of age. However, a four-week intranasal IFNβ treatment of HIVgp120tg mice starting at 3.5 months of age increases expression of CCL4 and concomitantly protects neuronal dendrites and pre-synaptic terminals in cortex and hippocampus from gp120-induced damage. Moreover,in vivoandin vitrodata suggests astrocytes are a major source of IFNβ-induced CCL4. Altogether, our results suggest exogenous IFNβ as a neuroprotective factor that has potential to amelioratein vivoHIVgp120-induced brain injury.