Sooty mangabey genome sequence provides insight into AIDS resistance in a natural SIV host.

In contrast to infections with human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques, SIV infection of a natural host, sooty mangabeys (Cercocebus atys), is non-pathogenic despite high viraemia. Here we sequenced and assembled the genome of a captive sooty mangabey. We conducted genome-wide comparative analyses of transcript assemblies from C. atys and AIDS-susceptible species, such as humans and macaques, to identify candidates for host genetic factors that influence susceptibility. We identified several immune-related genes in the genome of C. atys that show substantial sequence divergence from macaques or humans. One of these sequence divergences, a C-terminal frameshift in the toll-like receptor-4 (TLR4) gene of C. atys, is associated with a blunted in vitro response to TLR-4 ligands. In addition, we found a major structural change in exons 3-4 of the immune-regulatory protein intercellular adhesion molecule 2 (ICAM-2); expression of this variant leads to reduced cell surface expression of ICAM-2. These data provide a resource for comparative genomic studies of HIV and/or SIV pathogenesis and may help to elucidate the mechanisms by which SIV-infected sooty mangabeys avoid AIDS.

Tissue-specific transcriptional profiling of plasmacytoid dendritic cells reveals a hyperactivated state in chronic SIV infection.

HIV associated immune activation (IA) is associated with increased morbidity in people living with HIV (PLWH) on antiretroviral therapy, and remains a barrier for strategies aimed at reducing the HIV reservoir. The underlying mechanisms of IA have not been definitively elucidated, however, persistent production of Type I IFNs and expression of ISGs is considered to be one of the primary factors. Plasmacytoid DCs (pDCs) are a major producer of Type I IFN during viral infections, and are highly immunomodulatory in acute HIV and SIV infection, however their role in chronic HIV/SIV infection has not been firmly established. Here, we performed a detailed transcriptomic characterization of pDCs in chronic SIV infection in rhesus macaques, and in sooty mangabeys, a natural host non-human primate (NHP) species that undergoes non-pathogenic SIV infection. We also investigated the immunostimulatory capacity of lymph node homing pDCs in chronic SIV infection by contrasting gene expression of pDCs isolated from lymph nodes with those from blood. We observed that pDCs in LNs, but not blood, produced high levels of IFNα transcripts, and upregulated gene expression programs consistent with T cell activation and exhaustion. We apply a novel strategy to catalogue uncharacterized surface molecules on pDCs, and identified the lymphoid exhaustion markers TIGIT and LAIR1 as highly expressed in SIV infection. pDCs from SIV-infected sooty mangabeys lacked the activation profile of ISG signatures observed in infected macaques. These data demonstrate that pDCs are a primary producer of Type I IFN in chronic SIV infection. Further, this study demonstrated that pDCs trafficking to LNs persist in a highly activated state well into chronic infection. Collectively, these data identify pDCs as a highly immunomodulatory cell population in chronic SIV infection, and a putative therapeutic target to reduce immune activation.

Cushing Disease: Medical and Surgical Considerations.

Cushing disease is a disorder of hypercortisolemia caused by hypersecretion of adrenocorticotropic hormone by a pituitary adenoma and is a rare diagnosis. Cushing disease presents with characteristic clinical signs and symptoms associated with excess cortisol, but diagnosis is difficult and often relies on repeated and varied endocrinologic assays and neuroradiologic investigations. Gold standard treatment is surgical resection of adrenocorticotropic hormone-secreting pituitary adenoma, which is curative. Patients require close endocrinologic follow-up for maintenance of associated neuroendocrine deficiencies and surveillance for potential recurrence. Medications, radiation therapy, and bilateral adrenalectomy are alternative treatments for residual or recurrent disease.

Artificial neural networks predict the need for permanent cerebrospinal fluid diversion following posterior fossa tumor resection.

Background: Resection of posterior fossa tumors (PFTs) can result in hydrocephalus that requires permanent cerebrospinal fluid (CSF) diversion. Our goal was to prospectively validate a machine-learning model to predict postoperative hydrocephalus after PFT surgery requiring permanent CSF diversion. Methods: We collected preoperative and postoperative variables on 518 patients that underwent PFT surgery at our center in a retrospective fashion to train several statistical classifiers to predict the need for permanent CSF diversion as a binary class. A total of 62 classifiers relevant to our data structure were surveyed, including regression models, decision trees, Bayesian models, and multilayer perceptron artificial neural networks (ANN). Models were trained using the (N = 518) retrospective data using 10-fold cross-validation to obtain accuracy metrics. Given the low incidence of our positive outcome (12%), we used the positive predictive value along with the area under the receiver operating characteristic curve (AUC) to compare models. The best performing model was then prospectively validated on a set of 90 patients. Results: Twelve percent of patients required permanent CSF diversion after PFT surgery. Of the trained models, 8 classifiers had an AUC greater than 0.5 on prospective testing. ANNs demonstrated the highest AUC of 0.902 with a positive predictive value of 83.3%. Despite comparable AUC, the remaining classifiers had a true positive rate below 35% (compared to ANN, P < .0001). The negative predictive value of the ANN model was 98.8%. Conclusions: ANN-based models can reliably predict the need for ventriculoperitoneal shunt after PFT surgery.

Feasibility and Morbidity of Magnetic Resonance Imaging-Guided Stereotactic Laser Ablation of Deep Cerebral Cavernous Malformations: A Report of 4 Cases.

BACKGROUND: Magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy (MRgLITT) has been used successfully to treat epileptogenic cortical cerebral cavernous malformations (CCM). It is unclear whether MRgLITT would be as feasible or safe for deep CCMs. OBJECTIVE: To describe our experience with MRgLITT for symptomatic deep CCMs. METHODS: Patients' records were reviewed retrospectively. MRgLITT was carried out using a commercially available system in an interventional MRI suite with efforts to protect adjacent brain structures. Immediate postoperative imaging was used to judge ablation adequacy. Delayed postoperative MRI was used to measure lesion volume changes during follow-up. RESULTS: Four patients with CCM in the thalamus, putamen, midbrain, or subthalamus presented with persistent and disabling neurological symptoms. A total of 2 patients presented with disabling headaches and sensory disturbances and 2 with recurrent symptomatic hemorrhages, of which 1 had familial CCM. Patients were considered by vascular neurosurgeons to be poor candidates for open surgery or had refused it. Multiple trajectories were used in most cases. Adverse events included device malfunction with leakage of saline causing transient mass effect in one patient, and asymptomatic tract hemorrhage in another. One patient suffered an expected mild but persistent exacerbation of baseline deficits. All patients showed improvement from a previously aggressive clinical course with lesion volume decreased by 20% to 73% in follow-up. CONCLUSION: MRgLITT is feasible in the treatment of symptomatic deep CCM but may carry a high risk of complications without the benefit of definitive resection. We recommend cautious patient selection, low laser power settings, and conservative temperature monitoring in surrounding brain parenchyma.

Permanent Cerebrospinal Fluid Diversion in Adults With Posterior Fossa Tumors: Incidence and Predictors.

BACKGROUND: Posterior fossa tumors (PFTs) can cause hydrocephalus. Hydrocephalus can persist despite resection of PFTs in a subset of patients requiring permanent cerebrospinal fluid (CSF) diversion. Characteristics of this patient subset are not well defined. OBJECTIVE: To define preoperative and postoperative variables that predict the need for postoperative CSF diversion in adult patients with PFTs. METHODS: We surveyed the CNS (Central Nervous System) Tumor Outcomes Registry at Emory (CTORE) for patients who underwent PFT resection at 3 tertiary-care centers between 2006 and 2019. Demographic, radiographic, perioperative, and dispositional data were analyzed using univariate and multivariate models. RESULTS: We included 617 patients undergoing PFT resection for intra-axial (57%) or extra-axial (43%) lesions. Gross total resection was achieved in 62% of resections. Approximately 13% of patients required permanent CSF diversion/shunting. Only 31.5% of patients who required pre- or intraop external ventricular drain (EVD) placement needed permanent CSF diversion. On logistic regression, size, transependymal flow, use of perioperative EVD, postoperative intraventricular hemorrhage (IVH), and surgical complications were predictors of permanent CSF diversion. Preoperative tumor size was only independent predictor of postoperative shunting in patients with subtotal resection. In patients with intra-axial tumors, transependymal flow (P = .014), postoperative IVH (P = .001), surgical complications (P = .013), and extent of resection (P = .03) predicted need for shunting. In extra-axial tumors, surgical complications were the major predictor (P = .022). CONCLUSION: Our study demonstrates that presence of preoperative hydrocephalus in patients with PFT does not necessarily entail the need for permanent CSF diversion. We report the major predictive factors for needing permanent CSF diversion.

Macrophage-associated wound healing contributes to African green monkey SIV pathogenesis control.

Natural hosts of simian immunodeficiency virus (SIV) avoid AIDS despite lifelong infection. Here, we examined how this outcome is achieved by comparing a natural SIV host, African green monkey (AGM) to an AIDS susceptible species, rhesus macaque (RM). To asses gene expression profiles from acutely SIV infected AGMs and RMs, we developed a systems biology approach termed Conserved Gene Signature Analysis (CGSA), which compared RNA sequencing data from rectal AGM and RM tissues to various other species. We found that AGMs rapidly activate, and then maintain, evolutionarily conserved regenerative wound healing mechanisms in mucosal tissue. The wound healing protein fibronectin shows distinct tissue distribution and abundance kinetics in AGMs. Furthermore, AGM monocytes exhibit an embryonic development and repair/regeneration signature featuring TGF-ß and concomitant reduced expression of inflammatory genes compared to RMs. This regenerative wound healing process likely preserves mucosal integrity and prevents inflammatory insults that underlie immune exhaustion in RMs.

Author Correction: Macrophage-associated wound healing contributes to African green monkey SIV pathogenesis control.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

BALDR: a computational pipeline for paired heavy and light chain immunoglobulin reconstruction in single-cell RNA-seq data.

B cells play a critical role in the immune response by producing antibodies, which display remarkable diversity. Here we describe a bioinformatic pipeline, BALDR (BCR Assignment of Lineage using De novo Reconstruction) that accurately reconstructs the paired heavy and light chain immunoglobulin gene sequences from Illumina single-cell RNA-seq data. BALDR was accurate for clonotype identification in human and rhesus macaque influenza vaccine and simian immunodeficiency virus vaccine induced vaccine-induced plasmablasts and naïve and antigen-specific memory B cells. BALDR enables matching of clonotype identity with single-cell transcriptional information in B cell lineages and will have broad application in the fields of vaccines, human immunodeficiency virus broadly neutralizing antibody development, and cancer.BALDR is available at https://github.com/BosingerLab/BALDR .