Treatment Of HIV-associated Neurocognitive Disorders Research Articles

Neuroprotective Effect of 7,8-dihydroxyflavone in a Mouse Model of HIV-Associated Neurocognitive Disorder (HAND)

Treatment for HIV-associated neurocognitive disorders (HAND) remains elusive. 7,8-dihydroxyflavone (DHF), an analog of brain-derived neurotrophic factor (BDNF) and a high-affinity TrkB agonist, has been proposed as a viable therapeutic alternative to BDNF in crossing the Blood-Brain Barrier (BBB) and promoting growth, differentiation, maintenance, and survival of neurons. Here, we expand on our previous study investigating the therapeutic role of DHF on the cortical and hippocampal brain regions of the Tg26 mice, an animal model of HAND. We detected increased immunoreactivity for ion channels (SUR1, TRPM4) and the water channel aquaporin-4 (AQP4), suggesting an ionic and osmotic imbalance in the brains of Tg26 mice. Tg26 mice also exhibited loss of synaptic stability (SYN, SYP) and nicotinamide metabolism (NAMPT, SIRT1) that were associated with astrogliosis. Furthermore, Tg26 mice demonstrated increased iNOS and reduced HO-1/NRF2 expressions, implicating increased ER and oxidative stress. DHF treatment in Tg26 mice reversed these pathological changes. These data suggest crosstalk among TrkB, Akt, and related transcription factors (NF-κB, STAT3, and NRF2) as an underlying mechanism of Tg26-associated pathology in the brain. Finally, taken together with our prior study, these results further highlight a therapeutic role of DHF in promoting neuroprotection in HAND that may be applied in conjunction with current antiviral therapies.

An Integrative Approach to the Current Treatment of HIV-Associated Neurocognitive Disorders and the Implementation of Leukemia Inhibitor Factor as a Mediator of Neurocognitive Preservation.

HIV-associated neurocognitive disorders (HANDs) continue to impact patients despite antiretroviral therapy. A combination of antiretroviral therapies can diminish the HIV viral load to near undetectable levels, but fails to preserve neurocognitive integrity. The cytokine leukemia inhibitory factor (LIF) has shown neuroprotective properties that could mitigate neurodegeneration in HANDs. The LIF promotes neurogenesis, neural cell differentiation, and survival. Combination antiretroviral therapy reduces severe forms of HANDs, but neurocognitive impairment persists; additionally, some antiretrovirals have additional adverse neurotoxic effects. The LIF counteracts neurotoxic viral proteins and limits neural cell damage in models of neuroinflammation. Adding the LIF as an adjuvant therapy to enhance neuroprotection merits further research for managing HANDs. The successful implementation of the LIF to current therapies would contribute to achieving a better quality of life for the affected population.

A Focus on Aging, HIV/AIDS, and Neurocognitive Challenges: Examining Southern Nevada HIV Sector Providers' Awareness and Prospective Roles.

Although abundant research has been carried out to investigate the underlying mechanisms that may cause neurocognitive challenges among middle-aged and older people living with HIV/AIDS (PLWH), to monitor the prevalence rates of HIV-related neurocognitive deficits, and to identify factors related to the improvement of diagnostic screening tools, classification and nosology, and clinical and rehabilitative treatment of HIV-Associated Neurocognitive Disorder (HAND); to date, there have been only a few studies that have explored and examined the awareness and work experiences HIV sector healthcare and service providers have related to HAND. To address this research gap, we conducted a qualitative, community-based participatory research study and interviewed 12 HIV sector providers in Southern Nevada, USA, from January to April 2022. After performing a thematic analysis of our interviews, we were able to identify two major themes and several sub-themes. Under our first major theme, provider awareness and knowledge, we identified four sub-themes: (1) prior knowledge and current awareness; (2) lived experiences of patients and clients with neurocognitive challenges; (3) lack of knowledge as a barrier to providing needed care; and (4) continuing education and professional development. Under our second major theme, prospective provider roles, we identified three sub-themes: (1) early detection; (2) direct and practical support; and (3) appropriate and timely referrals. In this article, we discuss our findings and lessons learned from our study, as well as their implications for the future work of researchers and providers in the HIV sector related to improving care and support for people aging with HIV/AIDS and experiencing neurocognitive challenges.

A high-throughput screening assay for silencing established HIV-1 macrophage infection identifies nucleoside analogs that perturb H3K9me3 on proviral genomes.

HIV-infected macrophages are long-lived cells that represent a barrier to functional cure. Additionally, low-level viral expression by central nervous system (CNS) macrophages contributes to neurocognitive deficits that develop despite antiretroviral therapy (ART). We recently identified H3K9me3 as an atypical epigenetic mark associated with chronic HIV infection in macrophages. Thus, strategies are needed to suppress HIV-1 expression in macrophages, but the unique myeloid environment and the responsible macrophage/CNS-tropic strains require cell/strain-specific approaches. Here, we generated an HIV-1 reporter virus from a CNS-derived strain with intact auxiliary genes expressing destabilized luciferase. We employed this reporter virus in polyclonal infection of primary human monocyte-derived macrophages (MDM) for a high-throughput screen (HTS) to identify compounds that suppress virus expression from established macrophage infection. Screening ~6,000 known drugs and compounds yielded 214 hits. A secondary screen with 10-dose titration identified 24 meeting criteria for HIV-selective activity. Using three replication-competent CNS-derived macrophage-tropic HIV-1 isolates and viral gene expression readout in MDM, we confirmed the effect of three purine analogs, nelarabine, fludarabine, and entecavir, showing the suppression of HIV-1 expression from established macrophage infection. Nelarabine inhibited the formation of H3K9me3 on HIV genomes in macrophages. Thus, this novel HTS assay can identify suppressors of HIV-1 transcription in established macrophage infection, such as nucleoside analogs and HDAC inhibitors, which may be linked to H3K9me3 modification. This screen may be useful to identify new metabolic and epigenetic agents that ameliorate HIV-driven neuroinflammation in people on ART or prevent viral recrudescence from macrophage reservoirs in strategies to achieve ART-free remission. IMPORTANCE Macrophages infected by HIV-1 are a long-lived reservoir and a barrier in current efforts to achieve HIV cure and also contribute to neurocognitive complications in people despite antiretroviral therapy (ART). Silencing HIV expression in these cells would be of great value, but the regulation of HIV-1 in macrophages differs from T cells. We developed a novel high-throughput screen for compounds that can silence established infection of primary macrophages, and identified agents that downregulate virus expression and alter provirus epigenetic profiles. The significance of this assay is the potential to identify new drugs that act in the unique macrophage environment on relevant viral strains, which may contribute to adjunctive treatment for HIV-associated neurocognitive disorders and/or prevent viral rebound in efforts to achieve ART-free remission or cure.

Formulation of antiretroviral nanocrystals and development into a microneedle delivery system for potential treatment of HIV-associated neurocognitive disorder (HAND)

HIV/AIDS remains a major global public health issue. While antiretroviral therapy is effective at reducing the viral load in the blood, up to 50% of those with HIV suffer from some degree of HIV-associated neurocognitive disorder, due to the presence of the blood–brain barrier restricting drugs from crossing into the central nervous system and treating the viral reservoir there. One way to circumvent this is the nose-to-brain pathway. This pathway can also be accessed via a facial intradermal injection. Certain parameters can increase delivery via this route, including using nanoparticles with a positive zeta potential and an effective diameter of 200 nm or less. Microneedle arrays offer a minimally invasive, pain-free alternative to traditional hypodermic injections. This study shows the formulation of nanocrystals of both rilpivirine (RPV) and cabotegravir, followed by incorporation into separate microneedle delivery systems for application to either side of the face. Following an in vivo study in rats, delivery to the brain was seen for both drugs. For RPV, a Cmax was seen at 21 days of 619.17 ± 73.32 ng/g, above that of recognised plasma IC90 levels, and potentially therapeutically relevant levels were maintained for 28 days. For CAB, a Cmax was seen at 28 days of 478.31 ± 320.86 ng/g, and while below recognised 4IC90 levels, does indicate that therapeutically relevant levels could be achieved by manipulating final microaaray patch size in humans.

A modern view on the prevention and treatment of HIV-associated neurocognitive disorders

Acquired Immune Deficiency Syndrome (AIDS) is now considered one of the most global pandemics in human history. Despite the use of highly active antiretroviral therapy (HAART), HIV-1 infection is often accompanied by the development of CNS disorders, including neurocognitive disorders. The use of etiologic therapy has successfully prevented many of the possible terminal complications of the disease, but as patient survival time increases, the prevalence of cognitive impairment among AIDS patients is increasing. Theclinical manifestations of these disorders can rapidly progress from subtle attention deficits and behavioral disorders to the development of dementia. Diagnosing neurocognitive impairment in HIV-infected patients is usually difficult and requires consistent diagnostic procedures from the clinician, including initial screening and, if necessary, neuropsychiatric testing and neuroimaging. Early diagnosis and correction of neurocognitive impairment in HIV-infected individuals with adequate antiretroviral therapy is essential for successful treatment. The review also considers the use of drugs for the prevention and treatment of neurocognitive impairment, taking into account the peculiarities of persistence of the pathogen in the nervous system and the capabilities of modern medicine. One of the most promising methods of supporting therapy for such disorders is the delivery of antiretroviral drugs using various nanosystems (polymeric nanoparticles, lipid nanoparticles, nanogels, magnetic particles).

Physiological effects of physical activity on neurocognitive function in people living with HIV : a systematic review of intervention and observational studies

The inadequacy of antiretroviral therapy in the treatment of HIV-associated neurocognitive disorders paves a way for regular physical activity as a lifestyle modification alternative. However, uncertainty exists among scholars regarding the use of physical activity as a means of managing cognitive disorders among HIV-seropositive individuals. The objective of the review was to examine the potential therapeutic value of physical activity intervention in the rehabilitation of people living with HIV (PLWHIV) experiencing cognitive disorders. Undertaken in this study was a systematic literature review by narrative and quantitative synthesis examining studies from 2000 to 2019. Data sources for the review included the following electronic databases: Medline, PubMed, Cochrane Library, CINAHL (The Cumulative Index to Nursing and Allied Health Literature), Academic Search Complete, PsycINFO and relevant reference lists. The eligibility criteria for the selected studies included in the review were interventional and observational studies, which investigated the interaction of physical activity and cognitive function in adult PLWHIV. Fourteen studies met the inclusion criteria. The study outcomes were cognitive function, aerobic fitness and sociodemographic characteristics. Meta-analyses were executed using RevMan 5.3 and MedCalc, with alpha set at 0.05. A total of 2516 PLWHIV with a mean age of 54±8 years and education, 13±2 years participated in the studies reviewed. Men constituted a greater percentage (60%) of the study participants. Physical activity was not superior to control over cognitive function (Z=0.86; p=0.39; Tau2=61.79 and I2=94%). However, there was a significant correlation between physical activity and neurocognitive function (r=0.26; p<0.05). It was concluded that physical activity was not superior to control over cognitive function in PLWHIV with no reported cognitive deficit.

Rilpivirine as a potential candidate for the treatment of HIV-associated neurocognitive disorders (HAND).

As the HIV epidemic continues to contribute to global morbidity and mortality, the prevalence of HIV-associated neurological disorders (HAND) also continues to be a major concern in infected individuals, despite the widespread use of combination antiretroviral therapy. Therefore, current antiretroviral drugs should be able to reach therapeutic levels in the brain for the treatment of HAND. The brain distribution of the next-generation non-nucleoside reverse transcriptase inhibitor, rilpivirine (RPV) was investigated in healthy female Sprague-Dawley (SD) rats. The presented study involves the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to estimate the concentrations of RPV in plasma and brain homogenate samples. The use of matrix-assisted laser desorption/ionization mass spectrometry imaging(MALDI-MSI) provided regional spatial distribution of RPV in brain tissue sections. The localization of RPV was found to be relatively high in the hypothalamus, thalamus and corpus callosum, brain regions known to be associated with neurodegeneration during HAND (including the cerebral cortex). This study has shown that RPV has an excellent blood-brain barrier penetrability. Thus, in combination with other antiretroviral drugs, better central nervous system (CNS) protection against HAND can possibly be achieved.

Optimal treatment of HIV-associated neurocognitive disorders: myths and reality. A critical review.

Background:The aim of this study was to review the clinical data on the effectiveness of the pharmacotherapy of HIV-associated neurocognitive disorders (HANDs).Methods:A literature search of PubMed was performed (from January 1996 to October 2018) using the terms: ‘HIV-associated neurocognitive disorders’, ‘HIV-associated dementia’, ‘mild neurocognitive disorder (MND)’, ‘asymptomatic neurocognitive impairment (ANI)’, ‘adjuvant therapies’, ‘antiretroviral treatment (cART)’, ‘neurotoxicity’, ‘cART intensification’, ‘fluid markers’, ‘cerebrospinal fluid’, ‘protease inhibitors’, ‘nonnucleoside reverse transcriptase inhibitor’, ‘nucleoside reverse transcriptase inhibitors’, and ‘integrase strand transfer inhibitors’. Additional references were identified from a review of literature citations. All English language clinical studies of adjunctive therapies and neuronal markers were selected in order to evaluate a closer relationship between the early involvement and the onset of cognitive decline. We identified 407 relevant studies, of which 248 were excluded based on abstract analysis. Finally, we analyzed 35 articles, organizing the results by cART, adjuvant and neuronal markers (total of 7716 participants).Results:It is important to inform clinicians about the importance of accurate phenotyping of HIV patients, incorporating an array of markers relevant to HAND pathophysiology, in order to assess the individual’s risk and potential response to future personalized antiretroviral treatmentConclusion:So far, no clinical trials of HAND therapies are effective beyond optimal suppression of HIV replication in the central nervous system. Combination of validated neuronal markers should be used to distinguish between milder HAND subtypes and improve efficiency of clinical trials, after strict control of confounders.

Statistical Design of Experiment (DoE) based development and optimization of DB213 in situ thermosensitive gel for intranasal delivery

DB213 is an HIV-1 replication inhibitor targeting the Central Nervous System for the treatment of HIV-associated neurocognitive disorders. Current study aims to develop an in situ thermosensitive gelling system for intranasal delivery of DB213 facilitated by Statistical Design of Experiment (DoE) to conduct a more efficient experimentation by extracting the maximum amount of information from limited experiments. In our current study, information was extracted from twenty-five experimental designs from MODDE® Software and a mathematical model was successfully developed to predict formulations to achieve desired performance as well as to analyze relationships between the amount of Pluronic F-127, Pluronic F-68, Chitosan, DB213 and the performances of in situ thermosensitive gels. Based on DoE, in situ thermosensitive gels of 1% DB213 (F1) and 5% DB213 (F2) were developed for further in vivo bioavailability and brain uptake evaluations in Sprague-Dawley rats and C57BL/6 mice, respectively. In comparison to DB213 water solution, intranasal administrations of F1 at 1 mg/kg in rats and F2 at 25 mg/kg in mice demonstrated relative bioavailabilities of 145% and 165% with significant increase in brain uptake.

Paroxetine and fluconazole therapy for HIV-associated neurocognitive impairment: results from a double-blind, placebo-controlled trial.

Paroxetine and fluconazole have neuroprotective effects in an in vitro model of HIV protein-mediated neuronal injury. This study evaluated the safety, tolerability, and efficacy of both paroxetine and fluconazole for the treatment of HIV-associated neurocognitive disorder (HAND). A 24-week randomized double-blind, placebo-controlled 2×2 factorial design study was used. HIV+ individuals with cognitive impairment were enrolled in the 24-week trial. Participants were randomly assigned to one of four groups: (1) paroxetine 20mg/day, (2) fluconazole 100mg every 12h, (3) paroxetine and fluconazole, or (4) placebo. Safety, tolerability, and efficacy were evaluated. Forty-five HIV+ individuals were enrolled. Medications were well tolerated. Compared to no paroxetine arms, HIV+ individuals receiving paroxetine showed improved NPZ8 summary scores, (mean change=0.25 vs - 0.19, p=0.049), CalCAP sequential test reaction time (mean change=0.34 vs -0.23, p=0.014), Trail Making Part B test performance (mean change=0.49 vs - 0.33, p=0.041), and FAS verbal fluency (mean change=0.25 vs 0.02, p=0.020) but a decline in the Letter number sequencing test (mean change=- 0.40 vs 0.26, p=0.023). Biomarkers of cellular stress, inflammation, and neuronal damage were not affected by paroxetine. HIV+ individuals receiving fluconazole did not show a benefit in cognition and showed an increase in multiple markers of cellular stress compared to the no fluconazole arms. In conclusion, paroxetine was associated with improvement in a summary neuropsychological test measure and in several neuropsychological tests but worse performance in one neuropsychological test. Further studies of paroxetine for the treatment of HAND and to define its precise neuroprotective properties are warranted.

Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals.

The use of antiretroviral (ARV) drugs with central nervous system (CNS) penetration effectiveness (CPE) may be useful in the treatment of HIV-associated neurocognitive disorder (HAND) as well as targeting a CNS reservoir in strategies to achieve a functional cure for HIV. However, increased cognitive deficits are linked to at least one of these drugs (efavirenz). As mitochondrial dysfunction has been found with a number of ARVs, and as such can affect neuronal function, the objective of this study was to assess the effects of ARV with high CPE for toxicological profiles on presynaptic nerve terminal energy metabolism. This subcellular region is especially vulnerable in that a constant supply of ATP is required for the proper maintenance of neurotransmitter release and uptake supporting proper neuronal function. We evaluated the effects of acute treatment with ten different high CPE ARVs from five different drug classes on rat cortical and striatal nerve terminal bioenergetic function. While cortical nerve terminal bioenergetics were not altered, striatal nerve terminals exposed to efavirenz, nevirapine, abacavir, emtricitabine, zidovudine, darunavir, lopinavir, raltegravir, or maraviroc (but not indinavir) exhibit reduced mitochondrial spare respiratory capacity (SRC). Further examination of efavirenz and maraviroc revealed a concentration-dependent impairment of striatal nerve terminal maximal mitochondrial respiration and SRC as well as a reduction of intraterminal ATP levels. Depletion of ATP at the synapse may underlie its dysfunction and contribute to neuronal dysfunction in treated HIV infection.

Computational modeling of human dopamine transporter structures, mechanism and its interaction with HIV-1 transactivator of transcription.

This is a brief review of computational modeling studies on the detailed structures and mechanism of human dopamine transporter (hDAT), as well as its interaction with HIV-1 transactivator of transcription (Tat). Extensive molecular modeling, docking and dynamics simulations have resulted in reasonable structural models of hDAT in three typical conformational states, its dopamine uptake mechanism and its interaction with Tat. The obtained hDAT models in different conformational states and their complexes with dopamine and Tat have provided novel structural and mechanistic insights concerning how hDAT uptakes dopamine and how Tat affects the dopamine uptake by hDAT. The computational insights, that are consistent with available experimental data, should be valuable for future rational design of novel therapeutic strategies for treatment of HIV-associated neurocognitive disorders.

Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis.

HIV-1 infection of macrophages increases cathepsin B secretion and induces neuronal apoptosis, but the molecular mechanism remains unclear. We identified macrophage-secreted cathepsin B protein interactions extracellularly and their contribution to neuronal death in vitro. Cathepsin B was immunoprecipitated from monocyte-derived macrophage supernatants after 12 days postinfection. The cathepsin B interactome was identified by label-free tandem mass spectrometry and compared with uninfected supernatants. Proteins identified were validated by western blot. Neurons were exposed to macrophage-conditioned media in presence or absence of antibodies against cathepsin B and interacting proteins. Apoptosis was measured using TUNEL labeling. Immunohistochemistry of postmortem brain tissue samples from healthy, HIV-infected and Alzheimer's disease patients was performed to observe the ex-vivo expression of the proteins identified. Nine proteins co-immunoprecipitated differentially with cathepsin B between uninfected and HIV-infected macrophages. Serum amyloid P component (SAPC)-cathepsin B interaction increased in HIV-infected macrophage supernatants, while matrix metalloprotease 9 (MMP-9)-cathepsin B interaction decreased. Pre-treatment of HIV-infected macrophage-conditioned media with antibodies against cathepsin B and SAPC decreased neuronal apoptosis. The addition of MMP-9 antibodies was not neuro-protective SAPC was overexpressed in postmortem brain tissue from HIV-positive neurocognitive impaired patients compared with HIV positive with normal cognition and healthy controls, although MMP-9 expression was similar in all tissues. Inhibiting SAPC-cathepsin B interaction protects against HIV-induced neuronal death and may help to find alternative treatments for HIV-associated neurocognitive disorders.

Mass spectrometric phosphoproteome analysis of HIV-infected brain reveals novel phosphorylation sites and differential phosphorylation patterns.

To map the phosphoproteome and identify changes in the phosphorylation patterns in the HIV-infected and uninfected brain. Parietal cortex from individuals with and without HIV infection were lysed and trypsinized. The peptides were labeled with iTRAQ reagents, combined, phospho-enriched by titanium dioxide chromatography, and analyzed by LC-MS/MS with high resolution. Our phosphoproteomic workflow resulted in the identification of 112 phosphorylated proteins and 17 novel phosphorylation sites in all the samples that were analyzed. The phosphopeptide sequences were searched for kinase substrate motifs, which revealed potential kinases involved in important signaling pathways. The site-specific phosphopeptide quantification showed that peptides from neurofilament medium polypeptide, myelin basic protein, and 2'-3'-cyclic nucleotide-3' phosphodiesterase have relatively higher phosphorylation levels during HIV infection. This study has enriched the global phosphoproteome knowledge of the human brain by detecting novel phosphorylation sites on neuronal proteins and identifying differentially phosphorylated brain proteins during HIV infection. Kinases that lead to unusual phosphorylations could be therapeutic targets for the treatment of HIV-associated neurocognitive disorders.

HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism.

HIV-associated neurocognitive disorders afflict approximately half of HIV-infected patients. HIV-infected cells within the CNS release neurotoxic viral proteins such as the transactivator of transcription (Tat). Tat caused a biphasic change in NMDAR function; NMDA-evoked increases in intracellular Ca(2+) were initially potentiated following 16 h exposure to Tat and then adapted by gradually returning to baseline by 24 h. Following Tat-induced NMDAR potentiation, a RhoA/Rho-associated protein kinase (ROCK) signaling pathway was activated; a subsequent remodeling of the actin cytoskeleton reduced NMDA-evoked increases in intracellular Ca(2+) . Pharmacologic or genetic inhibition of RhoA or ROCK failed to affect potentiation, but prevented adaptation of NMDAR function. Activation of RhoA/ROCK signaling increases the formation of filamentous actin. Drugs that prevent changes to filamentous actin blocked adaptation of NMDAR function following Tat-induced potentiation, whereas stimulating either depolymerization or polymerization of actin attenuated NMDAR function. These findings indicate that Tat activates a RhoA/ROCK signaling pathway resulting in actin remodeling and subsequent reduction of NMDAR function. Adaptation of NMDAR function may be a mechanism to protect neurons from excessive Ca(2+) influx and could reveal targets for the treatment of HIV-associated neurocognitive disorders.

HIV‐1 protein Tat produces biphasic changes in NMDA‐evoked increases in intracellular Ca2+ concentration via activation of Src kinase and nitric oxide signaling pathways

HIV-associated neurocognitive disorders afflict about half of HIV-infected patients. HIV-infected cells shed viral proteins, such as the transactivator of transcription (Tat), which can cause neurotoxicity by over activation of NMDA receptors. Here, we show that Tat causes a time-dependent, biphasic change in NMDA-evoked increases in intracellular Ca(2+) concentration ([Ca(2+)]i). NMDA-evoked responses were potentiated following 2-h exposure to Tat (50 ng/mL). Tat-induced potentiation of NMDA-evoked increases in [Ca(2+)]i peaked by 8 h and then adapted by gradually reversing to baseline by 24 h and eventually dropping below control by 48 h. Tat-induced potentiation of NMDA-evoked responses was blocked by inhibition of lipoprotein receptor-related protein (LRP) or Src tyrosine kinase. Potentiation was unaffected by inhibition of nitric oxide synthase (NOS). However, NOS activity was required for adaptation. Adaptation was also prevented by inhibition of soluble guanylate cyclase (sGC) and cyclic guanosine monophosphate-dependent protein kinase G (PKG). Together, these findings indicate that Tat potentiates NMDA-evoked increases in [Ca(2+)]i via LRP-dependent activation of Src and that this potentiation adapts via activation of the NOS/sGC/PKG pathway. Adaptation may protect neurons from excessive Ca(2+) influx and could reveal targets for the treatment of HIV-associated neurocognitive disorders. HIV-associated neurocognitive disorders (HAND) afflict about half of HIV-infected patients. HIV-infected cells shed viral proteins, such as the transactivator of transcription (Tat), which can cause neurotoxicity by over activation of NMDA receptors (NMDARs). We show that HIV-1 Tat evoked biphasic changes in NMDA-evoked [Ca(2+) ]i responses. Initially, Tat potentiated NMDA-evoked responses following LRP-mediated activation of Src kinase. Subsequently, Tat-induced NMDAR potentiation adapted by activation of a NOS/sGC/PKG pathway that attenuated NMDA-evoked increases in [Ca(2+)]i . Adaptation may be a novel neuroprotective mechanism to prevent excessive Ca(2+) influx. Solid and dashed arrows represent direct and potentially indirect connections, respectively.

Update on HIV-Associated Neurocognitive Disorders

Neurocognitive disorders are a feared complication of HIV infection, especially in the post-antiretroviral era as patients are living longer. These disorders are challenging in terms of diagnosis and treatment. The clinical syndrome has evolved, driven in part by comorbidities such as aging, drug abuse, psychiatric illnesses, and a metabolic syndrome associated with the use of antiretroviral drugs. Additionally some individuals may develop a fulminant immune reconstitution syndrome. Hence, treatment of these patients needs to be individualized. The focus of research in the HIV field has recently switched towards elimination of the HIV reservoir as a means of combating long-term HIV complications. However, these approaches may be suitable for limited populations and might not be applicable once the HIV reservoir has been established in the brain. Further, all clinical trials using neuroprotective or anti-inflammatory drugs for treatment of HIV-associated neurocognitive disorders have been unsuccessful. Hence, neurological complications of HIV infection are the biggest challenge facing HIV researchers, and there is a critical need to develop new diagnostics and approaches for treatment of these disorders.

Targeting the Glutamatergic System for the Treatment of HIV-Associated Neurocognitive Disorders

The accumulation of excess glutamate in the extracellular space as a consequence of CNS trauma, neurodegenerative diseases, infection, or deregulation of glutamate clearance results in neuronal damage by excessive excitatory neurotransmission. Glutamate excitotoxicity is thought to be one of several mechanisms by which HIV exerts neurotoxicity that culminates in HIV-associated neurocognitive disorders (HAND). Excess glutamate is released upon HIV infection of macrophage/microglial cells and has been associated with neurotoxicity mediated by gp120, transactivator of transcription (Tat) and other HIV proteins. Several strategies have been used over the years to try to prevent glutamate excitotoxicity. Since the main toxic effects of excess glutamate are thought to be due to excitotoxicity from over activation of glutamate receptors, antagonists of these receptors have been popular therapeutic targets. Early work to ameliorate the effects of excess extracellular glutamate focused on NMDA receptor antagonism, but unfortunately, potent blockade of this receptor has been fraught with side effects. One alternative to direct receptor blockade has been the inhibition of enzymes responsible for the production of glutamate such as glutaminase and glutamate carboxypeptidase II. Another approach has been to regulate the transporters responsible for modulation of extracellular glutamate such as excitatory amino acid transporters and the glutamate-cystine antiporter. There is preliminary experimental evidence that these approaches have potential therapeutic utility for the treatment of HAND. These efforts however, are at an early stage where the next steps are dependent on the identification of drug-like inhibitors as well as the development of predictive neuroAIDS animal models.

Cognitive neurorehabilitation of HIV-associated neurocognitive disorders: a qualitative review and call to action.

Despite significant advances in the virologic management of HIV infection over the last two decades, effective treatments for HIV-associated neurocognitive disorders (HAND) remain elusive. While pharmacological interventions have yielded some success in improving neurocognitive outcomes in HIV, there is a dearth of rigorous studies examining the efficacy of cognitive rehabilitation for remediating HIV-associated neurocognitive impairment. This qualitative review summarizes and critiques the emerging literature on cognitive and behavioral treatments for HAND, which provides many reasons for optimism, but also has major limitations that underscore the scope of the work that lies ahead. Considering the notable real-world consequences of HAND, the development, validation, and clinical deployment of cognitive neurorehabilitation interventions tailored to the needs of persons living with HIV infection is a priority for clinical neuroAIDS investigators. In describing potential future directions for this endeavor, particular attention was paid to the application of cognitive neuropsychological principles in developing theory-driven approaches to managing HAND, improving everyday functioning, and enhancing HIV health outcomes.