HIV Infection and Depression Among Opiate Users in a US Epicenter of the Opioid Epidemic.

Using a mobile research facility, we enrolled 141 opioid users from a neighborhood of Philadelphia, an urban epicenter of the opioid epidemic. Nearly all (95.6%) met DSM-5 criteria for severe opioid use disorder. The prevalence of HIV infection (8.5%) was more than seven times that found in the general population of the city. Eight of the HIV-positive participants (67.0%) reported receiving antiretroviral treatment but almost all of them had unsuppressed virus (87.5%). The majority of participants (57.4%) reported symptoms consistent with major depressive disorder. Severe economic distress (60.3%) and homelessness were common (57%). Polysubstance use was nearly universal, 72.1% had experienced multiple overdoses and prior medication for opioid use disorder (MOUD) treatment episodes (79.9%), but few currently engaged in addiction care. The prevalence, multiplicity and severity of chronic health and socioeconomic problems highlight consequences of the current opioid epidemic and underscore the urgent need to develop integrated models of treatment.

RESUMEN: Utilizando un Centro de Investigación Móvil, inscribimos a 141 usuarios de opioides del vecindario de Filadelfia, un epicentro urbano de la epidemia de opioides. Casi todos (95,6%) cumplieron con los criterios del DSM-5 para el trastorno del uso severo del consumo de opioides. La prevalencia de la infección de VIH (8,5%) fue másﹶ de 7 veces superior a las encontrada en la población general de la ciudad. Ocho de los participantes con VIH positivo (67,0%) reportaron haber recibido tratamiento antirretroviral pero casi todos tuvieron virus no suprimido (87,5%). La mayoría de los participantes (57,4%) informaron síntomas compatibles con el Desorden Depresivo Mayor. La angustia severa por lo económico (60,3%) y las personas sin hogar fueron comunes (57%). El uso de múltiples sustancias fue casi universal, el 721% había experimentado múltiples sobredosis y previos medicamentos para el tratamiento del trastorno por consumo de opioides (MOUD) (79,9%), pero muy pocos estaban comprometidos con la atención a las adicciones. La prevalencia, la multiplicidad y la seriedad de los problemas de salud crónica y los problemas socioeconómicos destacan las consecuencias de la actual epidemia de opioides y subrayan la urgente necesidad de desarrollar nuevos modelos de tratamiento integrados.

Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV.

BACKGROUND: Many HIV infected individuals with suppressed viral loads experience chronic immune activation frequently developing neurological impairment designated as HIV associated neurocognitive disorder (HAND). Adjunctive therapies may reduce HIV associated inflammation and therefore decrease the occurrence of HAND. METHODS: We have conducted in vitro, animal and clinical studies of the neurokinin 1 receptor (NK1R) antagonist aprepitant in HIV/SIV infection. RESULTS: Aprepitant inhibits HIV infection of human macrophages ex vivo with an ED50 ~ 5 µM. When administered at 125 mg once daily for 12 months to SIV-infected rhesus macaques, aprepitant reduced viral load by approximately tenfold and produced anti-anxiolytic effects. The anti-viral and anti-anxiolytic effects occur at approximately the third month of dosing; and the effects are sustained throughout the duration of drug administration. Protein binding experiments in culture media and animal and human plasma indicate that the free fraction of aprepitant is lower than previously reported supporting usage of higher doses in vivo. The analysis of blood samples from HIV positive individuals treated for 2 weeks with aprepitant at doses up to 375 mg demonstrated reduced levels of pro-inflammatory cytokines including G-CSF, IL-6, IL-8 and TNFα. Decreased pro-inflammatory cytokines may reduce HIV comorbidities associated with chronic inflammation. CONCLUSIONS: Our results provide evidence for a unique combination of antiretroviral, anti-inflammatory and behavioral modulation properties of aprepitant in vitro and in vivo. These results provide robust support for a clinical exposure target above that recommended for chemotherapy-induced nausea and vomiting. Doses up to 375 mg once daily in HIV-infected patients still elicit sub-therapeutic exposure of aprepitant though effective plasma concentrations can be achievable by proper dose modulation.

The complement system, neuronal injury, and cognitive function in horizontally-acquired HIV-infected youth.

The complement system (C1q/C3) is a key mediator of synaptic pruning during normal development. HIV inappropriately induces C1q and C3 production in the brain, and reduces neuronal complement inhibition. HIV may thus alter neural connectivity in the developing brain by excessively targeting synapses for elimination. The resultant pattern of neuronal injury may fundamentally alter neurodevelopmental and cognitive processes differentially across ages. This study aimed to (1) measure the association between the cerebrospinal fluid (CSF) complement factors (C1q/C3) and a marker of neuronal injury (NFL) in HIV+ subjects; (2) quantify the differences in CSF C1q/C3 between HIV+ youth and older adults; and (3) define the relationship between CSF C1q/C3 and cognitive impairment in each age group. We performed a retrospective cross-sectional study of 20 HIV+ 18-24-year-old youth and 20 HIV+ 40-46-year-old adults with varying levels of cognitive impairment enrolled in the CNS Antiretroviral Therapy Effects Research study. We quantified C3, C1q, and NFL by ELISA in paired CSF/plasma specimens. We found that CSF C1q correlates with NFL in all subjects not receiving antiretroviral therapy (n = 16, rho = 0.53, p = 0.035) when extreme NFL outliers were eliminated (n = 1). There was no difference in plasma/CSF C1q or C3 between older adults and youth. In 18-24-year-old youth, a nearly significant (p = 0.052) elevation of CSF C1q expression was observed in cognitively impaired subjects compared to cognitively normal subjects. Further investigation into the role of the CNS complement system in the neuropathogenesis of HIV is warranted and should be considered in a developmentally specific context.

Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorders (HAND) affect up to 50 % of HIV-infected adults, independently predict HIV morbidity/mortality, and are associated with neuronal damage and monocyte activation. Cerebrospinal fluid (CSF) neurofilament subunits (NFL, pNFH) are sensitive surrogate markers of neuronal damage in several neurodegenerative diseases. In HIV, CSF NFL is elevated in individuals with and without cognitive impairment, suggesting early/persistent neuronal injury during HIV infection. Although individuals with severe cognitive impairment (HIV-associated dementia (HAD)) express higher CSF NFL levels than cognitively normal HIV-infected individuals, the relationships between severity of cognitive impairment, monocyte activation, neurofilament expression, and systemic infection are unclear. We performed a retrospective cross-sectional study of 48 HIV-infected adults with varying levels of cognitive impairment, not receiving antiretroviral therapy (ART), enrolled in the CNS Anti-Retroviral Therapy Effects Research (CHARTER) study. We quantified NFL, pNFH, and monocyte activation markers (sCD14/sCD163) in paired CSF/plasma samples. By examining subjects off ART, these correlations are not confounded by possible effects of ART on inflammation and neurodegeneration. We found that CSF NFL levels were elevated in individuals with HAD compared to cognitively normal or mildly impaired individuals with CD4+ T-lymphocyte nadirs ≤200. In addition, CSF NFL levels were significantly positively correlated to plasma HIV-1 RNA viral load and negatively correlated to plasma CD4+ T-lymphocyte count, suggesting a link between neuronal injury and systemic HIV infection. Finally, CSF NFL was significantly positively correlated with CSF pNFH, sCD163, and sCD14, demonstrating that monocyte activation within the CNS compartment is directly associated with neuronal injury at all stages of HAND.

Substance P enhances HIV-1 infection in human fetal brain cell cultures expressing full-length neurokinin-1 receptor.

The associations between the neurokinin-1 receptor (NK-1R), substance P (SP), and HIV-1 were investigated in neurosphere-derived cultures of microglial-depleted human fetal brain cells (HFBC). Full-length NK-1R was identified in HFBC cultures. SP treatment of the HFBC increased intracellular calcium mobilization and decreased electrical impedance, both of which were blocked by the NK-1R antagonist aprepitant. SP treatment of HIV-1-infected HFBC upregulated HIV-1 expression. These data show that human neural cells grown from neurospheres express functional full length NK-1R that is responsive to SP, and that SP enhanced HIV-1 infection in HBFC.

PET measurement of receptor occupancy as a tool to guide dose selection in neuropharmacology: are we asking the right questions?

Receptor occupancy studies are becoming commonplace for verifying drug mechanism of action and selecting early development candidates. Positron emission tomography (PET) has been applied to pharmacodynamic (PD) studies in several therapeutic areas including neurology, cardiology, and oncology. Prospective use of PET to define dosing requirements has been proposed particularly for central nervous system (CNS)-targeted drugs; however, correlations with clinical outcomes have been mostly anecdotal and not causally established.

Analog of somatostatin vapreotide exhibits biological effects in vitro via interaction with neurokinin-1 receptor.

OBJECTIVES: Vapreotide, a synthetic analog of somatostatin, has analgesic activity most likely mediated through the blockade of neurokinin-1 receptor (NK1R), the substance P (SP)-preferring receptor. The ability of vapreotide to interfere with other biological effects of SP has yet to be investigated. METHODS: We studied the ability of vapreotide to antagonize NK1R in three different cell types: immortalized U373MG human astrocytoma cells, human monocyte-derived macrophages (MDM) and a human embryonic kidney cell line, HEK293. Both U373MG and MDM express endogenous NK1R while HEK293 cells, which normally do not express NK1R, are stably transformed to express human NK1R (HEK293-NK1R). RESULTS: Vapreotide attenuates SP-triggered intracellular calcium increases and nuclear factor-κB activation in a dose-dependent manner. Vapreotide also inhibits SP-induced interleukin-8 and monocyte chemotactic protein-1 production in HEK293-NK1R and U373MG cell lines. Vapreotide inhibits HIV-1 infection of human MDM in vitro, an effect that is reversible by SP pretreatment. CONCLUSIONS: Our findings indicate that vapreotide has NK1R antagonist activity and may have a potential application as a therapeutic intervention in HIV-1 infection.

The glucocorticoid antagonist RU-486 suppresses HIV infectivity and replication.

The effects of RU-486, a glucocorticoid antagonist, on HIV infection and replication in depressed and nondepressed women were studied using ex vivo models of HIV infection. RU-486 treatment of cells decreased HIV reverse transcriptase activity of monocyte-derived macrophages in a model of acute infectivity. RU-486 also decreased HIV viral replication in the chronically-infected T-cell line ACH-2, but not in the promonocyte cell line U1. No differences were associated with depression status. Thus, glucocorticoid antagonism may suppress HIV infectivity and replication ex vivo. Studies to determine the role of glucocorticoid antagonists in the host defense against HIV should be performed.

The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Neurokinin 1 receptor isoforms and the control of innate immunity.

Substance P is the prototype tachykinin peptide and triggers a variety of biological effects in both the nervous and immune system. Two naturally occurring variants of the neurokinin 1 receptor (NK1R) mediate the effects of SP: a 'classic' full-length receptor and a truncated (tail-less) form that lacks 96 amino acid residues at the C-terminus. Most research has focused on the full length receptor and the truncated NK1R has not been extensively explored. Recent data demonstrate that truncated NK1R has important functional roles, including modulation of responses triggered by cytokines, chemotaxis of macrophages and regulation of HIV replication. Targeting the truncated NK1R with pharmacologic agents might result in novel therapeutic approaches in diseases which affect the immune system, including HIV disease.

Neurokinin-1 receptor (NK1-R) expression in the brains of SIV-infected rhesus macaques: implications for substance P in NK1-R immune cell trafficking into the CNS.

Recent studies suggest a link between neuropsychiatric disorders and HIV/SIV infection. Most evidence indicates that monocytes/macrophages are the primary cell type infected within the CNS and that they contribute to CNS inflammation and neurological disease. Substance P (SP), a pleotropic neuropeptide implicated in inflammation, depression, and immune modulation via interaction with its cognate receptor, the neurokinin 1 receptor (NK1-R), is produced by monocyte/macrophages. While the presence of NK1-R on neurons is well known, its role on cells of the immune system such as monocyte/macrophages is just beginning to emerge. Therefore, we have examined the expression of SP and NK1-R and their relationship to SIV/HIV encephalitis (SIVE/HIVE) lesions and SIV-infected cells. These studies demonstrated intense expression of SP and NK1-R in SIVE lesions, with macrophages being the principal cell expressing NK1-R. Interestingly, all of the SIV-infected macrophages expressed NK1-R. Additionally, we examined the functional role of SP as a proinflammatory mediator of monocyte activation and chemotaxis. These studies demonstrated that treatment of monocytes with SP elicited changes in cell-surface expression for CCR5 and NK1-R in a dose-dependent manner. Moreover, pretreatment with SP enhanced both SP- and CCL5-mediated chemotaxis. All of these findings suggest that SP and NK1-R are important in SIV infection of macrophages and the development of SIVE lesions.

Immune suppression and immune activation in depression.

Depression has been characterized as a disorder of both immune suppression and immune activation. Markers of impaired cellular immunity (decreased natural killer cell cytotoxicity) and inflammation (elevated IL-6, TNFα, and CRP) have been associated with depression. These immunological markers have been associated with other medical illnesses, suggesting that immune dysregulation may be a central feature common to both depression and to its frequent medical comorbidities. Yet the significant associations of findings of both immune suppression and immune activation with depression raise questions concerning the relationship between these two classes of immunological observations. Depressed populations are heterogeneous groups, and there may be differences in the immune profiles of populations that are more narrowly defined in terms of symptom profile and/or demographic features. There have been few reports concurrently investigating markers of immune suppression and immune activation in the same depressed individuals. An emerging pre-clinical literature suggests that chronic inflammation may directly contribute to the pathophysiology of immune suppression in the context of illnesses such as cancer and rheumatoid arthritis. This literature provides us with specific immunoregulatory mechanisms mediating these relationships that could also explain differences in immune disturbances between subsets of depressed individuals We propose a research agenda emphasizing the assessment of these immunoregulatory mechanisms in large samples of depressed subjects as a means to define the relationships among immune findings (suppression and/or activation) within the same depressed individuals and to characterize subsets of depressed subjects based on shared immune profiles. Such a program of research, building on and integrating our knowledge of the psychoneuroimmunology of depression, could lead to innovation in the assessment and treatment of depression and its medical comorbidities.

Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor.

The neurokinin-1 receptor (NK1R) has two naturally occurring forms that differ in the length of the carboxyl terminus: a full-length receptor consisting of 407 aa and a truncated receptor consisting of 311 aa. We examined whether there are differential signaling properties attributable to the carboxyl terminus of this receptor by using stably transfected human embryonic kidney (HEK293) cell lines that express either full-length or truncated NK1R. Substance P (SP) specifically triggered intracellular calcium increase in HEK293 cells expressing full-length NK1R but had no effect in the cells expressing the truncated NK1R. In addition, in cells expressing full-length NK1R, SP activated NF-kappaB and IL-8 mRNA expression, but in cells expressing the truncated NK1R, SP did not activate NF-kappaB, and it decreased IL-8 mRNA expression. In cells expressing full-length NK1R, SP stimulated phosphorylation of PKCdelta but inhibited phosphorylation of PKCdelta in cells expressing truncated NK1R. There are also differences in the timing of SP-induced ERK activation in cells expressing the two different forms of the receptor. Full-length NK1R activation of ERK was rapid (peak within 1-2 min), whereas truncated NK1R-mediated activation was slower (peak at 20-30 min). Thus, the carboxyl terminus of NK1R is the structural basis for differences in the functional properties of the full-length and truncated NK1R. These differences may provide important information toward the design of new NK1R receptor antagonists.

Neurokinin-1 receptor signaling induces a pro-inflammatory transcriptomic profile in CD16+ monocytes.

Neurokinin-1 receptor (NK1R) signaling can be immunomodulatory and it can lead to preferential transmigration of CD14+CD16+ monocytes across the blood brain barrier, potentially promoting the development of inflammatory neurological diseases, such as neuroHIV. To evaluate how NK1R signaling alters monocyte biology, RNA sequencing was used to define NK1R-mediated transcriptional changes in different monocyte subsets. The data show that NK1R activation induces a greater number of changes in CD14+CD16+ monocytes (152 differentially expressed genes), than in CD14+CD16- monocytes (36 genes), including increases in the expression of NF-κB and components of the NLRP3 inflammasome pathway. These results suggest that NK1R may alter the inflammatory state of CD14+CD16+ monocytes, influencing the development of neuroinflammation.

Effect of aprepitant on kynurenine to tryptophan ratio in cART treated and cART naïve adults living with HIV.

ABSTRACT: Changes in tryptophan metabolism affect human physiology including the immune system, mood, and sleep and are associated with human immunodeficiency virus (HIV) pathogenesis. This study investigates whether the treatment of HIV-infected individuals with the neurokinin-1 receptor antagonist, aprepitant, alters tryptophan metabolism.This study utilized archival samples from 3 phase 1B clinical trials "Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 Antagonist Aprepitant"-2 double-blinded, placebo-controlled, and 1 open-label study. We tested samples from a total of 57 individuals: 26 combination antiretroviral therapy (cART) naïve individuals receiving aprepitant, 19 cART naïve individuals receiving placebo, and 12 individuals on a ritonavir-containing cART regimen receiving aprepitant. We evaluated the effect of aprepitant on tryptophan metabolism by measuring levels of kynurenine and tryptophan in archival plasma samples and calculating the kynurenine to tryptophan ratio.Aprepitant treatment affected tryptophan metabolism in both cART treated and cART naïve individuals with more profound effects in patients receiving cART. While aprepitant treatment affected tryptophan metabolism in all HIV-infected patients, it only significantly decreased kynurenine to tryptophan ratio in cART treated individuals. Aprepitant treatment offers an opportunity to target inflammation and mood disorders frequently co-existing in chronic HIV infection.

Number of opioid overdoses and depression as a predictor of suicidal thoughts.

BACKGROUND: Opioid use disorders are associated with increased risk of suicide thoughts, attempts, and death. We explored key variables from two theories of the development of suicidal thoughts and attempts (the interpersonal and three-step theories of suicide) to understand possible mechanisms underlying the association between opioid use and suicide risk. We hypothesized that interpersonal connections, variables reflecting psychological and physical pain, and variables that reduce fear of death (prior overdoses and risk-taking behaviors) would be associated with increased risk of thoughts of suicide. METHODS: Participants (N = 141) were opioid users recruited from an epicenter of the opioid crisis in Philadelphia using a mobile research center and completed an interview to assess substance use, depression, medical comorbidities, and suicidal thoughts among other variables. RESULTS: Univariate analyses showed that prior history of overdose, diagnosis of depression, older age, homelessness, and interpersonal connection were each associated with increased likelihood of endorsing thoughts of death/suicide. Multivariable analyses revealed prior history of overdose and depression were the variables most strongly associated with risk for thoughts of suicide. CONCLUSIONS: Consistent with two theories of the development of suicidal thoughts and attempts, exposure to variables that reduce fear of death (e.g., overdoses) were associated with suicidal thoughts. In contrast, other risk-taking behaviors, medical comorbidities, and substance use were not key predictors of suicidal thoughts in this sample. Implications for targeted risk assessment among clinicians are discussed.

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Selective serotonin reuptake inhibitor suppression of HIV infectivity and replication.

OBJECTIVE: To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down-regulate human immunodeficiency virus (HIV) infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/acquired immune deficiency syndrome. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells and CD8(+) lymphocytes, key regulators of HIV infection. METHODS: Ex vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication in 48 depressed and nondepressed women. For both the acute and chronic infection models, HIV reverse transcriptase activity was measured in the citalopram treatment condition and the control condition. RESULTS: The SSRI significantly down-regulated the reverse transcriptase response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status. CONCLUSIONS: These studies suggest that an SSRI enhances natural killer/CD8 noncytolytic HIV suppression in HIV/acquired immune deficiency syndrome and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV.