TNFRSF11B computational development network construction and analysis between frontal cortex of HIV encephalitis (HIVE) and HIVE-control patients

<p>Abstract</p> <p>Background</p> <p><it>TNFRSF11B </it>computational development network construction and analysis of frontal cortex of HIV encephalitis (HIVE) is very useful to identify novel markers and potential targets for prognosis and therapy.</p> <p>Methods</p> <p>By integration of gene regulatory network infer (GRNInfer) and the database for annotation, visualization and integrated discovery (DAVID) we identified and constructed significant molecule <it>TNFRSF11B </it>development network from 12 frontal cortex of HIVE-control patients and 16 HIVE in the same GEO Dataset GDS1726.</p> <p>Results</p> <p>Our result verified <it>TNFRSF11B </it>developmental process only in the downstream of frontal cortex of HIVE-control patients (<it>BST2, DGKG, GAS1, PDCD4, TGFBR3, VEZF1 </it>inhibition), whereas in the upstream of frontal cortex of HIVE (<it>DGKG, PDCD4 </it>activation) and downstream (<it>CFDP1, DGKG, GAS1, PAX6 </it>activation; <it>BST2, PDCD4, TGFBR3, VEZF1 </it>inhibition). Importantly, we datamined that <it>TNFRSF11B </it>development cluster of HIVE is involved in T-cell mediated immunity, cell projection organization and cell motion (only in HIVE terms) without apoptosis, plasma membrane and kinase activity (only in HIVE-control patients terms), the condition is vital to inflammation, brain morphology and cognition impairment of HIVE. Our result demonstrated that common terms in both HIVE-control patients and HIVE include developmental process, signal transduction, negative regulation of cell proliferation, RNA-binding, zinc-finger, cell development, positive regulation of biological process and cell differentiation.</p> <p>Conclusions</p> <p>We deduced the stronger <it>TNFRSF11B </it>development network in HIVE consistent with our number computation. It would be necessary of the stronger <it>TNFRSF11B </it>development function to inflammation, brain morphology and cognition of HIVE.</p

Role of Histidine 547 of Human Dopamine Transporter in Molecular Interaction with HIV-1 Tat and Dopamine Uptake

HIV-1 Tat plays an important role in HIV-associated neurocognitive disorders (HAND) by disrupting neurotransmission including dopamine uptake by human dopamine transporter (hDAT). Previous studies have demonstrated that HIV-1 Tat directly binds to hDAT and some amino-acid mutations that attenuate the hDAT-Tat binding also significantly decreased dopamine uptake activity of hDAT. This combined computational-experimental study demonstrates that histidine-547 (H547) of hDAT plays a crucial role in the hDAT-Tat binding and dopamine uptake by hDAT, and that the H547A mutation can not only considerably attenuate Tat-induced inhibition of dopamine uptake, but also significantly increase the Vmax of hDAT for dopamine uptake. The finding of such an unusual hDAT mutant capable of both increasing the Vmax of hDAT for dopamine uptake and disrupting the hDAT-Tat binding may provide an exciting knowledge basis for development of novel concepts for therapeutic treatment of the HAND

HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity

HIV subtypes or clades differentially induce HIV-associated neurocognitive disorders (HAND) and substance abuse is known to accelerate HIV disease progression. The HIV-1 envelope protein gp120 plays a major role in binding and budding in the central nervous system (CNS) and impacts dopaminergic functions. However, the mechanisms utilized by HIV-1 clades to exert differential effects and the methamphetamine (METH)-associated dopaminergic dysfunction are poorly understood. We hypothesized that clade B and C gp120 structural sequences, modeling based analysis, dopaminergic effect, and METH potentiate neuronal toxicity in astrocytes. We evaluated the effect of clade B and C gp120 and/or METH on the DRD-2, DAT, CaMKs and CREBP transcription. Both the structural sequence and modeling studies demonstrated that clade B gp120 in V1-V4, α -2 and N-glycosylated sites are distinct from clade C gp120. The distinct structure and sequence variation of clade B gp120 differentially impact DRD-2, DAT, CaMK II and CaMK IV mRNA, protein and intracellular expression compared to clade C gp120. However, CREB transcription is upregulated by both clade B and C gp120, and METH co-treatment potentiated these effects. In conclusion, distinct structural sequences of HIV-1 clade B and C gp120 differentially regulate the dopaminergic pathway and METH potentiates neurotoxicity

Allosteric Modulatory Effects of SRI-20041 and SRI-30827 on Cocaine and HIV-1 Tat Protein Binding to Human Dopamine Transporter

Dopamine transporter (DAT) is the target of cocaine and HIV-1 transactivator of transcription (Tat) protein. Identifying allosteric modulatory molecules with potential attenuation of cocaine and Tat binding to DAT are of great scientific and clinical interest. We demonstrated that tyrosine 470 and 88 act as functional recognition residues in human DAT (hDAT) for Tat-induced inhibition of DA transport and transporter conformational transitions. Here we investigated the allosteric modulatory effects of two allosteric ligands, SRI-20041 and SRI-30827 on cocaine binding on wild type (WT) hDAT, Y470 H and Y88 F mutants. Effect of SRI-30827 on Tat-induced inhibition of [3H]WIN35,428 binding was also determined. Compared to a competitive DAT inhibitor indatraline, both SRI-compounds displayed a similar decrease (30%) in IC50 for inhibition of [3H]DA uptake by cocaine in WT hDAT. The addition of SRI-20041 or SRI-30827 following cocaine slowed the dissociation rate of [3H]WIN35,428 binding in WT hDAT relative to cocaine alone. Moreover, Y470H and Y88F hDAT potentiate the inhibitory effect of cocaine on DA uptake and attenuate the effects of SRI-compounds on cocaine-mediated dissociation rate. SRI-30827 attenuated Tat-induced inhibition of [3H]WIN35,428 binding. These observations demonstrate that tyrosine 470 and 88 are critical for allosteric modulatory effects of SRI-compounds on the interaction of cocaine with hDAT

Selective Behavioral Alterations In The HIV-1 Transgenic Rat: Implications For Diagnosis Of Pediatric HIV-1

Since the advent of combination antiretroviral therapy (cART), pediatric HIV-1 (PHIV) has evolved from a fatal disease to a chronic disease with children perinatally infected with HIV-1 surviving into adulthood. The HIV-1 transgenic (Tg) rat, which expresses 7 of the 9 HIV-1 genes constitutively throughout development, was used to investigate the early development of chronic neurological impairment in PHIV. Male and female Fischer HIV-1 Tg and F344N control rats, sampled from 35 litters, were repeatedly assessed during early development using multiple experimental paradigms, including somatic growth, locomotor activity, cross-modal prepulse inhibition (PPI) and gap-prepulse inhibition (gap-PPI). A rightward shift towards later eye opening was observed in HIV-1 Tg animals in comparison to controls. HIV-1 Tg animals exhibited delays in the development of the cholinergic inhibitory system, assessed using locomotor activity. Alterations in the development of the interstimulus interval (ISI) function were observed in HIV-1 Tg rats in comparison to control animals, assessed using PPI. Presence of the HIV-1 transgene was diagnosed with 91.4% accuracy using multiple behavioral assessments on PD 20 and 21. Selective early behavioral alterations observed in the HIV-1 Tg rats provide an opportunity for the development of a clinical diagnostic screening tool, which may improve the long-term outcome for children perinatally infected with HIV-1

The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice

Depression and psychostimulant abuse are common comorbidities among humans with immunodeficiency virus (HIV) disease. The HIV regulatory protein TAT is one of multiple HIV-related proteins associated with HIV-induced neurotoxicity. TAT-induced dysfunction of dopamine and serotonin systems in corticolimbic brain areas may result in impaired reward function, thus, contributing to depressive symptoms and psychostimulant abuse. Transgenic mice with doxycycline-induced TAT protein expression in the brain (TAT+, TAT- control) show neuropathology resembling brain abnormalities in HIV+ humans. We evaluated brain reward function in response to TAT expression, nicotine and methamphetamine administration in TAT+ and TAT- mice using the intracranial self-stimulation procedure. We evaluated the brain dopamine and serotonin systems with high-performance liquid chromatography. The effects of TAT expression on delay-dependent working memory in TAT+ and TAT- mice using the operant delayed nonmatch-to-position task were also assessed. During doxycycline administration, reward thresholds were elevated by 20% in TAT+ mice compared with TAT- mice. After the termination of doxycycline treatment, thresholds of TAT+ mice remained significantly higher than those of TAT- mice and this was associated with changes in mesolimbic serotonin and dopamine levels. TAT+ mice showed a greater methamphetamine-induced threshold lowering compared with TAT- mice. TAT expression did not alter delay-dependent working memory. These results indicate that TAT expression in mice leads to reward deficits, a core symptom of depression, and a greater sensitivity to methamphetamine-induced reward enhancement. Our findings suggest that the TAT protein may contribute to increased depressive-like symptoms and continued methamphetamine use in HIV-positive individuals

Molecular Mechanism: The Human Dopamine Transporter Histidine 547 Regulates Basal and HIV-1 Tat Protein-Inhibited Dopamine Transport

Abnormal dopaminergic transmission has been implicated as a risk determinant of HIV-1-associated neurocognitive disorders. HIV-1 Tat protein increases synaptic dopamine (DA) levels by directly inhibiting DA transporter (DAT) activity, ultimately leading to dopaminergic neuron damage. Through integrated computational modeling prediction and experimental validation, we identified that histidine547 on human DAT (hDAT) is critical for regulation of basal DA uptake and Tat-induced inhibition of DA transport. Compared to wild type hDAT (WT hDAT), mutation of histidine547 (H547A) displayed a 196% increase in DA uptake. Other substitutions of histidine547 showed that DA uptake was not altered in H547R but decreased by 99% in H547P and 60% in H547D, respectively. These mutants did not alter DAT surface expression or surface DAT binding sites. H547 mutants attenuated Tat-induced inhibition of DA transport observed in WT hDAT. H547A displays a differential sensitivity to PMA- or BIM-induced activation or inhibition of DAT function relative to WT hDAT, indicating a change in basal PKC activity in H547A. These findings demonstrate that histidine547 on hDAT plays a crucial role in stabilizing basal DA transport and Tat-DAT interaction. This study provides mechanistic insights into identifying targets on DAT for Tat binding and improving DAT-mediated dysfunction of DA transmission

Imaging of brain structural and functional effects in people with human immunodeficiency virus

Before the introduction of antiretroviral therapy, human immunodeficiency virus (HIV) infection was often accompanied by central nervous system (CNS) opportunistic infections and HIV encephalopathy marked by profound structural and functional alterations detectable with neuroimaging. Treatment with antiretroviral therapy nearly eliminated CNS opportunistic infections, while neuropsychiatric impairment and peripheral nerve and organ damage have persisted among virally suppressed people with HIV (PWH), suggesting ongoing brain injury. Neuroimaging research must use methods sensitive for detecting subtle HIV-associated brain structural and functional abnormalities, while allowing for adjustments for potential confounders, such as age, sex, substance use, hepatitis C coinfection, cardiovascular risk, and others. Here, we review existing and emerging neuroimaging tools that demonstrated promise in detecting markers of HIV-associated brain pathology and explore strategies to study the impact of potential confounding factors on these brain measures. We emphasize neuroimaging approaches that may be used in parallel to gather complementary information, allowing efficient detection and interpretation of altered brain structure and function associated with suboptimal clinical outcomes among virally suppressed PWH. We examine the advantages of each imaging modality and systematic approaches in study design and analysis. We also consider advantages of combining experimental and statistical control techniques to improve sensitivity and specificity of biotype identification and explore the costs and benefits of aggregating data from multiple studies to achieve larger sample sizes, enabling use of emerging methods for combining and analyzing large, multifaceted data sets. Many of the topics addressed in this article were discussed at the National Institute of Mental Health meeting Biotypes of CNS Complications in People Living with HIV, held in October 2021, and are part of ongoing research initiatives to define the role of neuroimaging in emerging alternative approaches to identifying biotypes of CNS complications in PWH. An outcome of these considerations may be the development of a common neuroimaging protocol available for researchers to use in future studies examining neurological changes in the brains of PWH

Behavioral and Voltammetric Analysis of Chronic Escitalopram Treatment to the HIV-1 Transgenic Rat: Implications for Comorbid HIV-1 and Clinical Depression

HIV-1 infection is a serious condition affecting approximately 37 million individuals. Between 30% and 60% of seropositive individuals will develop symptoms of clinical depression. These individuals are five times more likely to commit suicide than non-seropositive clinically depressed patients. Dysfunction in serotonergic and dopaminergic transmission has consistently been implicated in the pathogenesis of depression. Specifically, dysfunction in the prefrontal cortex and in the nucleus accumbens core region have been shown to be underlying factors in the trajectory of depression. Given these underlying neurological features, the present research employed behavioral testing and electrochemical recording in an attempt to elucidate the therapeutic efficacy of the SSRI escitalopram in treating HIV-1 mitigated depressive symptoms in a transgenic (Tg) rodent model of depression. The HIV-1 Tg rat contains seven of the nine genes present in the HIV viral genome and presents itself with impairments similar to those observed in human HIV-1 seropositive individuals. The HIV-1 Tg rat thus represents a non-infectious model for controlled HIV-1 exposure. Here, we report failure of the SSRI to attenuate behavioral and electrochemical alterations present in the HIV-1 Tg rat. Given the known variability of SSRI medication and previously documented individual differences to drug dosage found within the model, it is thus concluded that more research is required in order to firmly establish the global efficacy of escitalopram in treated comorbid HIV-1 clinical depression

HIV-1 Transgenic Rat: Selective Alterations In Motivation And Histological Examination Of Medium Spiny Neurons Of The Nucleus Accumbens

Motivational alterations in HIV-1+ individuals are associated with decreased performance on tasks involving frontal-subcortical circuitry and the nucleus accumbens. In the present study, the HIV-1 transgenic (Tg) rat was used to assess long-term HIV-1 viral protein exposure on motivated behavior using activity chambers (40x40cm) and voluntary wheel running. Adult ovariectomized female HIV-1 Tg animals (n=21) to F344 controls (n=26) were pair-housed under a 12:12 light/dark cycle. Voluntary running was measured with 34 cm-diameter running wheels for ~60 minutes/day for 3 ½ months. There were no significant differences between HIV-1 Tg and F344 control rats in voluntary wheel running during the light phase. Animals were subsequently run in the nocturnal phase of their light/dark cycle. The F344 controls continued to escalate their overall running distances and surpassed the stabilized HIV-1 Tg group after ~4 weeks of nocturnal running, until reaching their asymptotic plateau at week 11. Neither maximal running speed, nor the latency to initiate running or running bout length were significantly different between groups. However, the groups were different in the number of running bouts per session, as a function of the HIV-1 transgene. Collectively, the selective alterations in the motivation for voluntary wheel running and activity chamber locomotor activity, suggests a disruption of the motivational circuitry within the HIV-1 Tg rat brain. Examination of Medium Spiny Neurons of the nucleus accumbens showed significant alterations in dendritic spine length and spine head diameter. Further study of these alterations in spine parameters may help elucidate the mechanisms of motivational alterations in HIV-1+individuals