AZD5582 plus SIV-specific antibodies reduce lymph node viral reservoirs in antiretroviral therapy-suppressed macaques.

The main barrier to HIV cure is a persistent reservoir of latently infected CD4 T cells harboring replication-competent provirus that fuels rebound viremia upon antiretroviral therapy (ART) interruption. A leading approach to target this reservoir involves agents that reactivate latent HIV proviruses followed by direct clearance of cells expressing induced viral antigens by immune effector cells and immunotherapeutics. We previously showed that AZD5582, an antagonist of inhibitor of apoptosis proteins and mimetic of the second mitochondrial-derived activator of caspases (IAPi/SMACm), induces systemic reversal of HIV/SIV latency but with no reduction in size of the viral reservoir.

Central Vein Sign in Pediatric Multiple Sclerosis and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Background: The central vein sign (CVS) on brain magnetic resonance imaging (MRI) is a promising diagnostic marker for distinguishing adult multiple sclerosis (MS) from other demyelinating conditions, but its prevalence is not well-established in pediatric-onset multiple sclerosis (POMS) versus myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). MOGAD can mimic MS radiologically. This study seeks to determine the utility of CVS, together with other radiological findings, in distinguishing POMS from MOGAD in children.

Improving Early Recognition of Creutzfeldt-Jakob Disease Mimics.

Background And Objectives: Diagnostic criteria emphasize the use of sensitive and disease-specific tests to distinguish patients with rapidly progressive dementia (RPD) due to Creutzfeldt-Jakob disease (CJD) vs other causes (mimics). These tests are often performed in specialized centers, with results taking days to return. There is a need to leverage clinical features and rapidly reporting tests to distinguish patients with RPD due to CJD from those due to other causes (mimics) early in the symptomatic course.

Autoimmune Encephalitis Misdiagnosis in Adults.

Importance: Autoimmune encephalitis misdiagnosis can lead to harm.

Objective: To determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.

Design, Setting, And Participants: This retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), University of Washington in St Louis (n = 6), and University of Utah (n = 4).

Combined noncanonical NF-κB agonism and targeted BET bromodomain inhibition reverse HIV latency ex vivo.

Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with bromodomain (BD) and extraterminal domain protein inhibitors (BETi).

The CSF in neurosarcoidosis contains consistent clonal expansion of CD8 T cells, but not CD4 T cells.

The tissue-specific drivers of neurosarcoidosis remain poorly defined. To identify cerebrospinal fluid (CSF) specific, antigen-driven T and B cell responses, we performed single-cell RNA sequencing of CSF and blood cells from neurosarcoid participants coupled to T and B cell receptor sequencing. In contrast to pulmonary sarcoidosis, which is driven by CD4 T cells, we found CD8 T cell clonal expansion enriched in the neurosarcoid CSF.

Altered Response Pattern following AZD5582 Treatment of SIV-Infected, ART-Suppressed Rhesus Macaque Infants.

The "shock and kill" strategy for HIV-1 cure incorporates latency-reversing agents (LRA) in combination with interventions that aid the host immune system in clearing virally reactivated cells. LRAs have not yet been investigated in pediatric clinical or preclinical studies. Here, we evaluated an inhibitor of apoptosis protein (IAP) inhibitor (IAPi), AZD5582, that activates the noncanonical NF-κB (ncNF-κB) signaling pathway to reverse latency.

IFN-α blockade during ART-treated SIV infection lowers tissue vDNA, rescues immune function, and improves overall health.

Type I IFNs (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of HIV infection treated with antiretroviral therapy (ART) also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8+ T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-α antibody followed by an analytical treatment interruption (ATI).

Central nervous system intravascular lymphoma leading to rapidly progressive dementia.

Intravascular lymphoma is an uncommon subtype of B-cell lymphoma with neoplastic cells limited to the lumen of small blood vessels. We report a case of a 52-year-old man who presented with constitutional symptoms and rapidly progressive dementia. He was found to have diffuse leptomeningeal and faint parenchymal enhancement on magnetic resonance imaging and was subsequently diagnosed with intravascular lymphoma following a brain biopsy.

Training in Neurology: How Lessons Learned on Teaching, Well-being, and Telemedicine During the COVID-19 Pandemic Can Shape the Future of Neurology Education.

The COVID-19 pandemic has a disruptive effect on neurology education, necessitating creative adjustments in the delivery of education, clinical training, and well-being. In this article, a group of educators reflects on challenges and lessons learned on teaching, well-being, and telemedicine, and how these can shape the future of neurology education. Developing standardized, rigorous evaluation of teaching methods and telemedicine, reinforcing well-being resources, and promoting international educational collaborations can improve neurology training during and after the pandemic.

CD8 lymphocyte depletion enhances the latency reversal activity of the SMAC mimetic AZD5582 in ART-suppressed SIV-infected rhesus macaques.

Inducing latency reversal to reveal infected cells to the host immune system represents a potential strategy to cure HIV infection. In separate studies, we have previously shown that CD8 T cells may contribute to the maintenance of viral latency and identified a novel SMAC mimetic/IAP inhibitor (AZD5582) capable of reversing HIV/SIV latency by activating the non-canonical (nc) NF-κB pathway. Here, we use AZD5582 in combination with antibody-mediated depletion of CD8α cells to further evaluate the role of CD8 T cells in viral latency maintenance.

Characterization of Apo-Form Selective Inhibition of Indoleamine 2,3-Dioxygenase*.

Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest.

SMAC Mimetic Plus Triple-Combination Bispecific HIVxCD3 Retargeting Molecules in SHIV.C.CH505-Infected, Antiretroviral Therapy-Suppressed Rhesus Macaques.

The "shock-and-kill" human immunodeficiency virus type 1 (HIV-1) cure strategy involves latency reversal followed by immune-mediated clearance of infected cells. We have previously shown that activation of the noncanonical NF-κB pathway using an inhibitor of apoptosis (IAP), AZD5582, reverses HIV/simian immunodeficiency virus (SIV) latency. Here, we combined AZD5582 with bispecific HIVxCD3 DART molecules to determine the impact of this approach on persistence.

Treatment of Progressive Multifocal Leukoencephalopathy Using Immune Restoration.

Progressive multifocal leukoencephalopathy (PML) is a viral disease of the brain associated with immunodeficiency, immune suppressing medications, and malignancy. In the absence of effective anti-viral therapy for the causative JC virus, immune restoration has emerged as the critical therapeutic alternative. The evolving treatment of PML (and other rare JC virus-associated neurologic syndromes) requires consideration of baseline immune functioning and comorbid diseases while selecting from a number of therapeutic options to restore an effective immune response.

DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors.

We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane , had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead .

Gut-Resident Lactobacillus Abundance Associates with IDO1 Inhibition and Th17 Dynamics in SIV-Infected Macaques.

Gut microbes can profoundly modulate mucosal barrier-promoting Th17 cells in mammals. A salient feature of HIV/simian immunodeficiency virus (SIV) immunopathogenesis is the loss of Th17 cells, which has been linked to increased activity of the immunomodulatory enzyme, indoleamine 2,3-dioxygenase 1 (IDO 1). The role of gut microbes in this system remains unknown, and the SIV-infected rhesus macaque provides a well-described model for HIV-associated Th17 loss and mucosal immune disruption.

Gut epithelial barrier and systemic inflammation during chronic HIV infection.

Objective: Microbial translocation and innate immune action characterize HIV infection. Continued gut mucosal dysfunction during treatment and its relationship to CD4 T-cell recovery has not been well described.

Design: A cross-sectional study was performed of antiretroviral therapy (ART)-suppressed (immunologic responders with CD4 > 500 cells/μl and immunologic nonresponders with CD4 < 350 cells/μl), untreated HIV-infected, and seronegative participants consenting to gut biopsies and a blood draw.

Discordance between peripheral and colonic markers of inflammation during suppressive ART.

Objective: Persistent systemic inflammation is associated with the inability of some HIV-infected patients to normalize circulating CD4 T-cell levels after years of suppressive antiretroviral therapy. In this study, we sought to understand whether such systemic inflammation is also associated with detectable signs of inflammation in biopsies from the rectosigmoid colon.

Design: Immunologic and virological parameters were studied in the peripheral blood and in rectosigmoid colon biopsies from individuals with viral suppression for at least 2 years and with peripheral CD4 T-cell levels of <350 cells per cubic millimeter (immunologic nonresponders, n = 18) or >500 cells per cubic millimeter (immunologic responders, n = 16).