Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques

Despite successful control of viremia, many HIV-infected individuals given antiretroviral therapy (ART) exhibit residual inflammation, which is associated with non–AIDS-related morbidity and mortality and may contribute to virus persistence during ART. Here, we investigated the effects of IL-21 administration on both inflammation and virus persistence in ART-treated, SIV-infected rhesus macaques (RMs). Compared with SIV-infected animals only given ART, SIV-infected RMs given both ART and IL-21 showed improved restoration of intestinal Th17 and Th22 cells and a more effective reduction of immune activation in blood and intestinal mucosa, with the latter maintained through 8 months after ART interruption. Additionally, IL-21, in combination with ART, was associated with reduced levels of SIV RNA in plasma and decreased CD4⁺ T cell levels harboring replication-competent virus during ART. At the latest experimental time points, which were up to 8 months after ART interruption, plasma viremia and cell-associated SIV DNA levels remained substantially lower than those before ART initiation in IL-21–treated animals but not in controls. Together, these data suggest that IL-21 supplementation of ART reduces residual inflammation and virus persistence in a relevant model of lentiviral disease and warrants further investigation as a potential intervention for HIV infection.     

Placental Hofbauer cells assemble and sequester HIV-1 in tetraspanin-positive compartments that are accessible to broadly neutralizing antibodies

Introduction

Within monocyte-derived macrophages, HIV-1 accumulates in intracellular virus-containing compartments (VCCs) that are inaccessible to the external environment, which implicate these cells as latently infected HIV-1 reservoirs. During mother-to-child transmission of HIV-1, human placental macrophages (Hofbauer cells (HCs)) are viral targets, and have been shown to be infected in vivo and sustain low levels of viral replication in vitro; however, the risk of in utero transmission is less than 7%. The role of these primary macrophages as viral reservoirs is largely undefined. The objective of this study is to define potential sites of viral assembly, accumulation and neutralization in HCs given the pivotal role of the placenta in preventing HIV-1 infection in the mother-infant dyad.

Methods

Term placentae from 20 HIV-1 seronegative women were obtained following caesarian section. VCCs were evaluated by 3D confocal and electron microscopy. Colocalization R values (Pearson''s correlation) were quantified with colocalization module of Volocity 5.2.1. Replication kinetics and neutralization studies were evaluated using p24 ELISA.

Results

We demonstrate that primary HCs assemble and sequester HIV-1_BaL in intracellular VCCs, which are enriched in endosomal/lysosomal markers, including CD9, CD81, CD63 and LAMP-1. Following infection, we observed HIV-1 accumulation in potentially acidic compartments, which stained intensely with Lysotracker-Red. Remarkably, these compartments are readily accessible via the cell surface and can be targeted by exogenously applied small molecules and HIV-1-specific broadly neutralizing antibodies. In addition, broadly neutralizing antibodies (4E10 and VRC01) limited viral replication by HIV-1-infected HCs, which may be mediated by FcγRI.

Conclusions

These findings suggest that placental HCs possess intrinsic adaptations facilitating unique sequestration of HIV-1, and may serve as a protective viral reservoir to permit viral neutralization and/or antiretroviral drug entry in utero.     

Medicinal applications of (benz)imidazole‐ and indole‐based macrocycles

Macrocyclic chemistry is one of the emerging research areas in the chemical science. Macrocyclic compounds continue to attract significant attention due to their numerous possible applications particularly in the areas like biology, catalysis and industry. This review article summarizes the developments and advances in synthesis and medicinal applications of macrocyclic compounds derived from (benz)imidazole‐ and indole‐based heterocycles. Important medicinal applications of (benz)imidazole‐ and indole‐based macrocycles include antimicrobial and anticancer activities. The representative lead compounds in each series of macromolecules have been discussed. All these initial lead breakthroughs help validate the great potential of (benz)imidazole‐ and indole‐based macrocyclic compounds as a class of effective medicinal agents.     

FDC:TFH Interactions within Cervical Lymph Nodes of SIV-Infected Rhesus Macaques

Cerebrospinal fluid (CSF) drains via the lymphatic drainage pathway. This lymphatic pathway connects the central nervous system (CNS) to the cervical lymph node (CLN). As the CSF drains to CLN via the dural and nasal lymphatics, T cells and antigen presenting cells pass along the channels from the subarachnoid space through the cribriform plate. Human immunodeficiency virus (HIV) may also egress from the CNS along this pathway. As a result, HIV egressing from the CNS may accumulate within the CLN. Towards this objective, we analyzed CLNs isolated from rhesus macaques that were chronically-infected with simian immunodeficiency virus (SIV). We detected significant accumulation of SIV within the CLNs. SIV virion trapping was observed on follicular dendritic cells (FDCs) localized within the follicular regions of CLNs. In addition, SIV antigens formed immune complexes when FDCs interacted with B cells within the germinal centers. Subsequent interaction of these B cells with CD4+ T follicular helper cells (T_FHs) resulted in infection of the latter. Of note, 73% to 90% of the T_FHs cells within CLNs were positive for SIV p27 antigen. As such, it appears that not only do the FDCs retain SIV they also transmit them (via B cells) to T_FHs within these CLNs. This interaction results in infection of T_FHs in the CLNs. Based on these observations, we infer that FDCs within the CLNs have a novel role in SIV entrapment with implications for viral trafficking.     

Predictors of poor outcome in patients with posterior reversible encephalopathy syndrome

Purpose: Posterior reversible encephalopathy syndrome (PRES) is an acute neurotoxic syndrome that, although characteristically reversible, can be fatal or result in long-term disability in a subset of patients. Our aim was to identify factors associated with poor discharge outcome in PRES patients. Materials and methods: We retrospectively reviewed the clinical and radiological records of all patients with PRES admitted at our tertiary care medical center from 2007 to 2014. They were divided based their modified Rankin Score at discharge and compared for their baseline variables, clinical, laboratory and imaging features. Poor outcome was defined by a modified Rankin scale 2–6 and was subdivided based on the primary mechanism that led to poor outcome. Results: Out of 100 PRES subjects, 36% had poor discharge outcomes. Factors associated with poor outcomes on univariate analysis were history of diabetes mellitus, coma, high Charlson comorbidity index, post-transplantation, autoimmune condition, lack of systolic or diastolic hypertension, elevated blood urea nitrogen and involvement of the corpus callosum. On multivariate analysis, only prior diabetes mellitus odd ratio (OR) = 6.8 (95% CI 1.1–42.1, p = 0.04), corpus callosum involvement (OR = 11.7; 95% CI 2.4–57.4, p = 0.00) were associated with poor outcome. Poor outcome also correlated with increased length of hospital stay (OR = 7.9; 95% CI 1.3–49.7, p = 0.03). Conclusion: Large prospective studies incorporating serial blood glucose values and advanced imaging studies are required to validate these findings.     

Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain

The perinatal brain requires a tightly regulated iron transport system. Iron regulatory proteins (IRPs) 1 and 2 are cytosolic proteins that regulate the stability of mRNA for the two major cellular iron transporters, transferrin receptor (TfR) and divalent metal transporter-1 (DMT-1). We studied the localization of IRPs, their change in expression during perinatal development, and their relationship to TfR and DMT-1 in rat brain between postnatal days (PND) 5 and 15. Twelve-micron frozen coronal sections of fixed brain tissue were obtained from iron-sufficient Sprague-Dawley rat pups on PND 5, 10, and 15, and were visualized at 20 to 1,000x light microscopy for diaminobenzidine activity after incubation with specific primary IRP-1, IRP-2, DMT-1, and TfR antibodies and a universal biotinylated secondary and tertiary antibody system. IRP and transport protein expression increased in parallel over time. IRP1, IRP2, and DMT-1 were partially expressed in the choroid plexus epithelial cells at PND 5 and 10, and fully expressed at PND 15. The cerebral blood vessels and ependymal cells strongly expressed IRP1, IRP2, and DMT-1 as early as PND 5. Substantive TfR staining was not seen in the choroid plexus or ependyma until PND 15. Glial and neuronal expression of IRP1, IRP2, DMT-1, and TfR in cortex, hippocampal subareas and striatum increased over time, but showed variability in cell number and intensity of expression based on brain region, cell type, and age. These developmental changes in IRP and transporter expression suggest potentially different time periods of brain structure vulnerability to iron deficiency or iron overload.     

Should laparoscopic cholecystectomy be performed in patients with thick-walled gallbladder?

Background/Purpose Laparoscopic cholecystectomy is the procedure of choice for patients with symptomatic cholelithiasis. This procedure is contraindicated in patients with gall-bladder cancer (GBC) because of fear of dissemination of the disease. One of the findings raising the suspicion of GBC is a thick-walled gallbladder (TWGB).Methods A prospective study of patients with TWGB was done over a period of 10 months at a tertiary-level referral hospital in northern India. We studied the clinical profiles, investigations (ultrasound [US] and computerized tomography [CT]) and management plans in these patients.Results A total of 60 patients were included in the study. After cholecystectomy, histopathology of gallbladders showed GBC in 2 (3.3%) patients. The remaining 58 patients had chronic cholecystitis, of whom 28 (48%) had xanthogranulomatous variant chronic cholecystitis. Cholecystectomy by the laparoscopic method was attempted in 46 (77%) patients and by open technique in the remaining 14 (23%) patients. Laparoscopic cholecystectomy was successful in 40 of the 46 (87%) patients in whom it was attempted. Obscure anatomy, suspicion of GBC, and bile duct injury were the causes of conversion, in the remaining 13% (6/46). None of the 11 patients who had a CT examination because of clinical or US suspicion of malignancy turned out to have GBC at final histology. Both the cases of GBC in this study were incidental findings on final histopathology.Conclusions Laparoscopic cholecystectomy can be successfully performed in the majority of patients with diffuse TWGB, with appropriate selection. There is, however, an increased chance of conversion to open cholecystectomy in these patients. If there is an intraoperative suspicion of GBC, early conversion to open cholecystectmy and frozen section/imprint cytology will help to decide the further treatment during surgery.     

HIV-1 clade-C-associated "ALS"-like disorder: first report from India

A patient of ALS-like disorder in an HIV-1 clade-C-infected heterosexual male is being reported. A 37-year-old gentleman presented with subacute, progressive asymmetrical onset of weakness and wasting of upper limbs associated with brisk muscle stretch reflexes and without any sensory or sphincter involvement. While nerve conduction tests were normal, the EMG of proximal and distal limb muscles on both sides revealed evidence of denervation and reinnervation. Routine blood and urine tests and investigations for underlying causes of motor neuron disease were noncontributory. He was HIV-1, subtype clade C seropositive. A diagnosis of HIV-related anterior horn cell disease was considered and zidovudine, lamivudine and nevirapine were started. After 1 month, there was a subjective improvement of 10% and objective improvement in strength of muscles of proximal upper limb on both sides by one grade power on MRC scale. Reports of amyotrophic lateral sclerosis (ALS)-like illness in HIV are sparse. The reversibility of "ALS"-like features in this subgroup of patients might offer an insight into the pathogenesis of amyotrophic lateral sclerosis. This is a first report of ALS-like illness caused by subtype C of HIV-1 strain.     

Natural radioactivity in the soil samples of Coastal Karnataka of South India

Studies on radiation level and radionuclide distribution in the region of Coastal Karnataka, India, were undertaken. The purpose of this study is to provide baseline data on radiation level and radionuclide distribution in the region for the future assessment of the impact of the nuclear and thermal power stations that are being set up in the region. Further, this study may reveal information on the transportation of radionuclides in the environment. The external gamma dose rates in air have been measured throughout Coastal Karnataka using a sensitive plastic scintillometer. The measured dose rates include both terrestrial and cosmic ray components. The gamma dose rates in air range from 26 to 174 nGy h(-1) with a median value of 74 nGy h(-1). The activities of naturally occurring radionuclides in the soil samples of the region were measured using HPGe gamma ray spectrometry, and the resulting doses in air were calculated. The activity of 40K varies from 61.0 to 316.7 Bq kg(-1) with a median of 117.5 Bq kg(-1); the activity of 226Ra varies from 20.1 to 62.3 Bq kg(-1) with a median value 35.0 Bq kg(-1) and that of 232Th from 14.3 to 48.6 Bq kg(-1) with a median value of 29.8 Bq kg(-1). The mean absorbed dose rate in air due to naturally occurring radionuclides is found to be 41.5 nGy h(-1). In addition to this, the correlations between 226Ra and 40K, 232Th and 40K, and 226Ra and 232Th were computed from the results of the concentration of these naturally occurring radionuclides. A weak correlation was observed between 226Ra and 40K and between 232Th and 40K while a moderately good correlation was observed between 226Ra and 232Th. The results of these systematic investigations are presented and discussed in this paper.