HIV-1 interaction with an O-glycan-specific bacterial lectin enhances virus infectivity and resistance to neutralization by antibodies.

Bacteria dysbiosis has been associated with an increased risk of HIV-1 transmission and acquisition. The prevalent idea is that bacteria dysbiosis compromises mucosal integrity and promotes inflammatory conditions to cause recruitment and activation of immune cells that harbor or are targeted by HIV-1. However, it is also possible that HIV-1 directly binds bacteria or bacterial products to impact virus infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The Streptococcal Siglec-like lectin SLBR-N, which is part of the fimbriae shrouding the bacteria surface and recognizes α2,3 sialyated O-linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with O-glycan-binding plant lectins, signifying the importance of O-glycans. Conversely, N-glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to O-glycans on HIV-1 Env, and increase HIV-1 resistance to broadly neutralizing antibodies targeting different regions of Env. Hence, this study highlights the potential contribution of O-glycans in promoting HIV-1 infection through the exploitation of O-glycan-binding lectins from commensal bacteria at the mucosa.

HIV-1 interaction with an O-glycan-specific bacterial lectin enhances virus infectivity and resistance to neutralizing antibodies.

Bacteria dysbiosis and its accompanying inflammation or compromised mucosal integrity is associated with an increased risk of HIV-1 transmission. However, HIV-1 may also bind bacteria or bacterial products to impact infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The Streptococcal Siglec-like lectin SLBR-N, a part of the fimbriae shrouding the bacteria surface that recognizes α2,3 sialyated O-linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with O-glycan-binding plant lectins, signifying the importance of O-glycans. N-glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to O-glycans on HIV-1 Env, and increase HIV-1 resistance to neutralizing antibodies targeting different regions of Env. This study highlights the potential contribution of O-glycan-binding lectins from commensal bacteria at the mucosa in promoting HIV-1 infection.

The Clinical Spectrum and Occurrence of Major Infections in Hospitalized Children With Nephrotic Syndrome.

Background Nephrotic syndrome (NS) is one of the most common renal ailments in the pediatric population. The management of NS with major infections remains a challenge to pediatricians and pediatric nephrologists, as it is associated with increased morbidity and mortality. In this study, we aimed to know the clinical spectrum and occurrence of major infections in hospitalized children with NS. Methods This prospective, observational study was conducted over a period of two years among hospitalized NS children from one year to 18 years. The clinical spectrum and hospital course were studied in detail, and the data generated were analyzed to obtain valid results. Results A total of 101 hospitalizations of 66 children were assessed for the occurrence of infective complications. The incidence rate of infective complications among the hospitalized nephrotics was 29.7%. Urinary tract infection (UTI) was the commonest infective complication, followed by spontaneous bacterial peritonitis (SBP). Other infective complications observed were pneumonia, enteric fever, methicillin-resistant Staphylococcus aureus (MRSA) sepsis, tuberculosis, and varicella. Conclusion Infective complications are quite common among NS patients, where appropriate identification and prompt treatment could reduce morbidity and mortality.

Risk factors and occurrence of chronic kidney disease following acute kidney injury in Children.

Background: Chronic kidney disease (CKD) is an irreversible progressive condition with diverse etiologies among which acute kidney injury (AKI) is increasingly being recognized as an important one. Methods: This was a prospective observational study of pediatric intensive care unit (PICU) patients admitted with different etiologies, at a tertiary care hospital for children in Kashmir India, between October 2018 and September 2020. AKI was defined as an increase in absolute serum creatinine (SCr) ≥0.3 mg/dL or by a percentage increase in SCr 50% and/or by a decrease in urine output to <0.5 mL/kg/h for >6 hours (h). Besides analysis of AKI and associated PICU mortality, post-AKI patients after discharge were kept on follow-up for complete 1 year. Results: From 119 enrolled patients with AKI with no preexisting risk factors, 5.6% (n = 8/119) developed CKD. The AKI-associated mortality rate after 48 h of PICU stay was 13.4% (n = 16/119). At time of discharge from hospital, elevated blood pressure (BP) (n = 5/8) and subnephrotic proteinuria (n = 3/8) were the statistically significant sequels of AKI (P value <0.001) for progression to CKD. After 3 months of follow-up, elevated BP (n = 7/8) and subnephrotic proteinuria (n = 3/8) were significantly associated with progression to CKD at 1 year (P < 0.005). Conclusions: Occurrence of CKD after an attack of AKI was not uncommon and the risk of long-term consequences in the form of hypertension, proteinuria, and CKD is significant, which may be much higher than observed. It is prudent that all post-AKI PICU discharged patients must be monitored for the long-term consequences of AKI.

Résumé Contexte: La maladie rénale chronique (CKD) est une condition progressive irréversible avec diverses étiologies parmi lesquelles une lésion rénale aiguë (AKI) est de plus en plus reconnue comme importante. Méthodes: Il s'agissait d'une étude observationnelle prospective des patients de l'unité de soins intensifs pédiatriques (USIC) admis avec différentes étiologies, dans un hôpital de soins tertiaires pour les enfants du Cachemire, entre octobre 2018 et septembre 2020. L'AKI a été défini comme une augmentation de la créatinine sérique absolue (SCR) ≥ 0,3 mg / dL ou par un pourcentage d'augmentation du SCR 50% et / ou par une diminution de la production d'urine à <0,5 ml / kg / h pendant> 6 heures (H). Outre l'analyse de l'AKI et de la mortalité par USIC associée, les patients post-AKI après libération ont été maintenus sur le suivi pendant 1 an. Résultats: De 119 patients inscrits atteints d'AKI sans facteurs de risque préexistants, 5,6% (n = 8/119) ont développé une CKD. Le taux de mortalité associé à l'AKI après 48 h de séjour PICU était de 13,4% (n = 16/119). Au moment de la sortie de l'hôpital, une pression artérielle élevée (BP) (n = 5/8) et une protéinurie subnéphrotique (n = 3/8) étaient les suites statistiquement significatives de AKI (valeur p <0,001) pour la progression vers CKD. Après 3 mois de suivi - UP, une BP élevée (n = 7/8) et une protéinurie subnéphrotique (n = 3/8) ont été significativement associées à la progression vers la CKD à 1 an (p <0,005). Conclusions: La présence de CKD après une attaque d'AKI n'était pas rare et le risque de conséquences à long terme sous forme d'hypertension, de protéinurie et de CKD est significatif, ce qui peut être beaucoup plus élevé que celle observée. Il est prudent que tous les patients inscrits post-AKI PUCU doivent être surveillés pour les conséquences à long terme de l'AKI. Mots-clés: Blessures rénales aiguës, enfants, soins intensifs, mortalité, résultats.

HIV-1 Envelope Glycan Composition as a Key Determinant of Efficient Virus Transmission via DC-SIGN and Resistance to Inhibitory Lectins.

The HIV-1 envelope (Env) surface is shrouded with an assortment of oligomannose-, hybrid-, and complex-type glycans that enable virus interaction with carbohydrate-recognizing lectins. This study examined the importance of glycan heterogeneity for HIV-1 transmission through the trans-infection pathway by the host mannose-binding lectin DC-SIGN. A diversity of glycan content was observed among HIV-1 strains and associated with varying degrees of trans-infection via DC-SIGN and sensitivity to trans-infection blockage by antiviral lectins. When Env glycans were modified to display only the oligomannose type, DC-SIGN-mediated virus capture was enhanced; however, virus trans-infection was diminished because of increased degradation, which was alleviated by incorporation with hybrid-type glycans. Amino acid changes in the Env signal peptide (SP) modulated the Env glycan content, leading to alterations in DC-SIGN-dependent trans-infection and virus sensitivity to antiviral lectins. Hence, SP variation and glycosylation that confer varied types of oligosaccharides to HIV-1 Env are critical determinants for virus fitness and phenotypic diversity.

Heterogeneity in glycan composition on the surface of HIV-1 envelope determines virus sensitivity to lectins.

Lectins that target N-glycans on the surface of HIV-1 envelope (Env) glycoprotein have the potential for use as antiviral agents. Although progress has been made in deciphering the molecular details of lectin and Env glycan interaction, further studies are needed to better understand Env glycan heterogeneity among HIV-1 isolates and its influence on virus-neutralization sensitivity to lectins. This study evaluated a panel of lectins with fine specificity for distinct oligosaccharides and assessed their ability to inhibit infection of HIV-1 viruses known to have differing sensitivity to anti-HIV Env antibodies. The results showed that HIV-1 isolates have different sensitivity to lectins specific for α1-3Man, α1-6Man, and α1-2Man binding lectins. Considering that lectins exclusively recognize the oligosaccharide components of virus Env, these data suggest that glycan heterogeneity among HIV-1 isolates may explain this differential sensitivity. To evaluate this further, chronic and acute viruses were produced in the presence of different glycosidase inhibitors to express more homogenous glycans. Viruses enriched for α1-2Man terminating Man5-9GlcNAc2 glycans became similarly sensitive to α1-2Man-binding lectins. The α1-3Man- and α1-6Man-binding lectins also were more potent against viruses expressing predominantly Man5GlcNAc2 and hybrid type glycans with terminal α1-3Man and α1-6Man. Furthermore, lectin-mediated inhibition was competitively alleviated by mannan and this effect was augmented by enrichment of mannose-type glycans on the virus. In addition, while Env of viruses enriched with mannose-type glycans were sensitive to Endo-H deglycosylation, Env of untreated viruses were partially resistant, indicating that HIV-1 Env glycans are heterogeneously comprised of complex, hybrid, and mannose types. Overall, our data demonstrate that HIV-1 isolates display differential sensitivity to lectins, in part due to the microheterogeneity of N-linked glycans expressed on the surface of the virus Env glycoprotein.

Modulation of Antibody Responses to the V1V2 and V3 Regions of HIV-1 Envelope by Immune Complex Vaccines.

Prophylactic HIV vaccines must elicit antibodies (Abs) against the virus envelope glycoproteins (Env) to effectively prevent HIV infection. We investigated a vaccine platform that utilizes immune complexes made of Env proteins gp120 and monoclonal Abs (mAbs) against different gp120 epitopes. We previously observed alterations in V3 antigenicity upon formation of certain gp120/mAb complexes and demonstrated the ability of these complexes to modulate the elicitation of V3 Ab responses. However, the effects on the V1V2 domain, an important target for Abs that correlate with vaccine-induced protection against HIV, have not been studied, nor have immune complex vaccines made with non-B subtype Env. This study compared subtypes B (JRFL) and CRF_01.AE (A244) Env gp120 proteins in complex with selected gp120-specific mAbs. Allosteric and antigenic changes were detected on these immune complexes, indicating that gp120/mAb interaction induces alterations on the Env surface that may modify the Env immunogenic properties. To evaluate this idea, mice were immunized with gp120/mAb complexes or their uncomplexed gp120 counterparts. The overall serum IgG titers elicited against gp120 were comparable, but a marked skewing toward V1V2 or V3 was evident and dependent on the gp120 strain and the specificity of the mAb used to form the complexes. Compared with uncomplexed gp120JRFL, gp120JRFL complexed with CD4bs or V1V2 mAbs, but not with C2 or V3 mAbs, elicited V3 Abs of greater titers and breadth, and Abs more capable of neutralizing tier 1 virus. Epitope mapping revealed a shift to a more conserved site in the V3 crown. However, the complexes did not enhance V1V2 Ab response, and the elicited V1V2 Abs were not cross-reactive. This profile contrasts with Ab responses to gp120A244/mAb complexes. Notably, gp120A244/mAb complexes induced higher levels of V1V2 Abs with some cross-reactivity, while also stimulating weak or strain-specific V3 Abs. Sera from gp120A244/mAb complex-immunized animals displayed no measurable virus neutralization but did mediate Ab-dependent cellular phagocytosis, albeit at levels similar to that induced by gp120A244 alone. These data indicate the potential utility of immune complexes as vaccines to shape Ab responses toward or away from Env sites of interest.

Short Communication: Manα1-2Man-Binding Anti-HIV Lectins Enhance the Exposure of V2i and V3 Crown Neutralization Epitopes on the V1/V2 and V3 Hypervariable Loops of HIV-1 Envelope.

This study aimed to explore the contribution of high-mannose glycans in the masking of conserved V3 crown (GPG) and V2i epitopes on the hypervariable loops of most exposed distal surface of HIV-1 Env. Using lectins specific to Manα1-2Man residue containing Man6-9GlcNAc2 glycans extensively decorating HIV-1 Env, we found that Manα1-2Man-binding lectins enhance the exposure of these partially and transiently exposed epitopes and consequentially increase the neutralization strength of antibodies against these epitopes.

Morbidity and Mortality Pattern in Late Preterm Infants at a Tertiary Care Hospital in Jammu & Kashmir, Northern India.

INTRODUCTION: The morbidity and mortality pattern in late preterm infants is higher than term infants (gestational age ≥ 37weeks). The main reason behind that is the relative physiologic and metabolic immaturity, though there is no significant difference in the weight or the size of the two groups. AIM: The present study was undertaken to study the incidence, early neonatal morbidity and mortality (within first 7 days of life) in late preterm infants (34 - 36 6/7 weeks). MATERIALS AND METHODS: It was a hospital based prospective study conducted from April 2012 to March 2013. The study was conducted in the Department of Paediatrics and Neonatology at G.B. Pant General Hospital and Department of Gynaecology and Obstetrics L.D hospital and G.B. pant general hospital, (associated hospitals of Government Medical College, Srinagar). RESULTS: A total of 4100 neonates were included in the study. Incidence of late preterm neonates was 11.58 %. Three hundred sixty five (76.8%) of late preterm and 965 (28.3%) of term infants had at least one of the predefined neonatal conditions. Late preterm infants were at significantly higher risk for overall morbidity due to any cause (p<0.0001), respiratory morbidity (p<0.0001), mechanical ventilation (p=0.0002), jaundice (p<0.0001), hypoglycaemia (p<0.0001), and sepsis (p<0.0001) Perinatal asphyxia (p= 0.186). Early neonatal mortality in late preterm neonates was 2.5% or 25/1000 live births. CONCLUSION: Compared with term infants, late preterm infants are at high risk for overall morbidity, respiratory morbidity, and need of mechanical ventilation, jaundice, hypoglycaemia & sepsis. They also have a higher mortality as compared to term neonates.