Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody

Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. However, vaccine design is complicated by concern that elicited antibodies (Abs) may cross-react with other flaviviruses that share a similar envelope protein, such as dengue virus, West Nile virus, and yellow fever virus. This cross-reactivity may worsen symptoms of a subsequent infection through Ab-dependent enhancement. To better understand the neutralizing Ab response and risk of Ab-dependent enhancement, further information on germline Ab binding to ZIKV and the maturation process that gives rise to potently neutralizing Abs is needed. Here we use binding and structural studies to compare mature and inferred-germline Ab binding to envelope protein domain III of ZIKV and other flaviviruses. We show that affinity maturation of the light-chain variable domain is important for strong binding of the recurrent VH3-23/VK1-5 neutralizing Abs to ZIKV envelope protein domain III, and identify interacting residues that contribute to weak, cross-reactive binding to West Nile virus. These findings provide insight into the affinity maturation process and potential cross-reactivity of VH3-23/VK1-5 neutralizing Abs, informing precautions for protein-based vaccines designed to elicit germline versions of neutralizing Abs

Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques.

Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody-envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires

The Role of Kappa Opioid Receptors on the Serotonergic Neurons in the Dorsal Raphe Nucleus in the Dysphoric Component of Chronic Pain

Chronic pain has both a sensory and an affective component. The links between chronic pain and affective disorders such as depression have been widely shown, with up to 85% of those with chronic pain also suffering from severe depression. When this comorbidity exists, the prognosis is worse, chronic pain is increased, and it is less responsive to treatment. Between 2003 and 2014, the percentage of people who committed suicide who also had chronic pain rose by almost 3 percentage points. The kappa opioid receptor, KOR, has been implicated in the link between chronic pain and depression. The expression and function of KOR and its ligand, dynorphin, are both enhanced in chronic pain. Conditioned place aversion (CPA), a measure of aversion to a paired stimulus, is enhanced in chronic pain states compared to non-pathological states, and is driven by KORs. It has been shown that ablating or inhibiting KORs on all serotonergic neurons throughout the central nervous system is sufficient to block this KOR mediated place aversion. We hypothesized that KOR on serotonergic neurons projecting from the dorsal raphe nucleus (DRN) is responsible for the enhanced KOR agonist-induced aversion in chronic pain states. To test this, we ablated KOR from serotonergic neurons in the DRN and assessed the effect on the development of aversion using the conditioned place preference/aversion (CPP/A) paradigm. We confirmed that U50,488, a small molecule KOR agonist, produces enhanced CPA in chronic pain mice. The chronic constriction injury used in our chronic pain model increased mechanical responsiveness, suggesting the presence of mechanical allodynia. Ablating KOR on the serotonergic neurons in the DRN blocked CPA, suggesting that KOR on serotonergic neurons in the DRN may indeed be responsible for agonist-induced CPA. We also found that U50,488-mediated analgesia is intact in animals that lack KOR in serotonergic neurons in the DRN, showing that KOR analgesia derived from spinal KOR remains intact

Supplements, Diets and Other Complementary and Alternative Interventions in Adolescent Mental Health

Background: Complementary and alternative medicine (CAM) has become increasingly popular over the past 20 years and is used by many adolescents and their families. CAM includes a host of integrative approaches whose difference from traditional medicine center around its holistic rather than compartmentalized approach to the patient, in which evaluation of health and well-being considers the mind, body, and spirit. Methods: This article provides an overview of both pharmacologic and non-pharmacologic approaches, with a focus on 1) how CAM can be used in clinical practice; 2) how to best choose amongst available approaches guided by research findings that provide information to maximize safety and efficacy. Two hypothetical cases illustrate how to apply the research base of evidence to patients and thus avoid diagnostic pitfalls and safety concerns. Results: Current research points to the efficacy of CAM in adult and adolescent populations and the efficacy of interventions that include attention to good nutrition, regular exercise, sunlight, and hygiene, especially as these interventions may prevent or reduce the incidence of conduct disorder. Recent studies suggest that CAM treatments can improve overall functioning and reduce difficulties such as insomnia, depression and aggression that occur due to anxiety, attentional deficits, and mood disorders. Conclusions: It is important to acknowledge the current public perception that CAM treatments are less likely to cause serious adverse effects as compared to conventional treatments. More studies of adolescent populations critical to confirm which complementary and alternative medicine treatments are both safe and efficacious. An informed open-minded attitude to non-conventional approaches has the potential to improve outcomes and trust amongst parents, adolescents and mainstream medical and behavioral health staff

Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques.

Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody-envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires