A reflection on HIV/AIDS research after 25 years

Dr. Robert C. Gallo provides a personal reflection on the 25 year history of AIDS

Integrin αvβ5 is a primary receptor for adenovirus in CAR-negative cells

<p>Abstract</p> <p>Background</p> <p>Viruses bind to specific cellular receptors in order to infect their hosts. The specific receptors a virus uses are important factors in determining host range, cellular tropism, and pathogenesis. For adenovirus, the existing model of entry requires two receptor interactions. First, the viral fiber protein binds Coxsackie and Adenovirus Receptor (CAR), its primary cellular receptor, which docks the virus to the cell surface. Next, viral penton base engages cellular integrins, coreceptors thought to be required exclusively for internalization and not contributing to binding. However, a number of studies reporting data which conflicts with this simple model have been published. These observations have led us to question the proposed two-step model for adenovirus infection.</p> <p>Results</p> <p>In this study we report that cells which express little to no CAR can be efficiently transduced by adenovirus. Using competition experiments between whole virus and soluble viral fiber protein or integrin blocking peptides, we show virus binding is not dependent on fiber binding to cells but rather on penton base binding cellular integrins. Further, we find that binding to low CAR expressing cells is inhibited specifically by a blocking antibody to integrin αvβ5, demonstrating that in these cells integrin αvβ5 and not CAR is required for adenovirus attachment. The binding mediated by integrin αvβ5 is extremely high affinity, in the picomolar range.</p> <p>Conclusions</p> <p>Our data further challenges the model of adenovirus infection in which binding to primary receptor CAR is required in order for subsequent interactions between adenovirus and integrins to initiate viral entry. In low CAR cells, binding occurs through integrin αvβ5, a receptor previously thought to be used exclusively in internalization. We show for the first time that integrin αvβ5 can be used as an alternate binding receptor.</p

Crystal Structure and Size-Dependent Neutralization Properties of HK20, a Human Monoclonal Antibody Binding to the Highly Conserved Heptad Repeat 1 of gp41

The human monoclonal antibody (mAb) HK20 neutralizes a broad spectrum of primary HIV-1 isolates by targeting the highly conserved heptad repeat 1 (HR1) of gp41, which is transiently exposed during HIV-1 entry. Here we present the crystal structure of the HK20 Fab in complex with a gp41 mimetic 5-Helix at 2.3 Å resolution. HK20 employs its heavy chain CDR H2 and H3 loops to bind into a conserved hydrophobic HR1 pocket that is occupied by HR2 residues in the gp41 post fusion conformation. Compared to the previously described HR1-specific mAb D5, HK20 approaches its epitope with a different angle which might favor epitope access and thus contribute to its higher neutralization breadth and potency. Comparison of the neutralization activities of HK20 IgG, Fab and scFv employing both single cycle and multiple cycle neutralization assays revealed much higher potencies for the smaller Fab and scFv over IgG, implying that the target site is difficult to access for complete antibodies. Nevertheless, two thirds of sera from HIV-1 infected individuals contain significant titers of HK20-inhibiting antibodies. The breadth of neutralization of primary isolates across all clades, the higher potencies for C-clade viruses and the targeting of a distinct site as compared to the fusion inhibitor T-20 demonstrate the potential of HK20 scFv as a therapeutic tool

Embryology and bony malformations of the craniovertebral junction

BACKGROUND: The embryology of the bony craniovertebral junction (CVJ) is reviewed with the purpose of explaining the genesis and unusual configurations of the numerous congenital malformations in this region. Functionally, the bony CVJ can be divided into a central pillar consisting of the basiocciput and dental pivot and a two-tiered ring revolving round the central pivot, comprising the foramen magnum rim and occipital condyles above and the atlantal ring below. Embryologically, the central pillar and the surrounding rings descend from different primordia, and accordingly, developmental anomalies at the CVJ can also be segregated into those affecting the central pillar and those affecting the surrounding rings, respectively. DISCUSSION: A logical classification of this seemingly unwieldy group of malformations is thus possible based on their ontogenetic lineage, morbid anatomy, and clinical relevance. Representative examples of the main constituents of this classification scheme are given, and their surgical treatments are selectively discussed

A Hierarchical Taxonomy of Psychopathology Can Transform Mental Health Research

For more than a century, research on psychopathology has focused on categorical diagnoses. Although this work has produced major discoveries, growing evidence points to the superiority of a dimensional approach to the science of mental illness. Here we outline one such dimensional system-the Hierarchical Taxonomy of Psychopathology (HiTOP)-that is based on empirical patterns of co-occurrence among psychological symptoms. We highlight key ways in which this framework can advance mental-health research, and we provide some heuristics for using HiTOP to test theories of psychopathology. We then review emerging evidence that supports the value of a hierarchical, dimensional model of mental illness across diverse research areas in psychological science. These new data suggest that the HiTOP system has the potential to accelerate and improve research on mental-health problems as well as efforts to more effectively assess, prevent, and treat mental illness

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Evaluation of a mental health drop-in centre offering brief transdiagnostic psychological assessment and treatment for children and adolescents with long-term physical conditions and their families: a single-arm, open, non-randomised trial.

BACKGROUND: Children and young people with long-term physical conditions have significantly elevated mental health needs. Transdiagnostic, brief psychological interventions have the potential to increase access to evidence-based psychological treatments for patients who attend health services primarily for physical health needs. OBJECTIVE: A non-randomised study was conducted to assess the impact of brief, transdiagnostic psychological interventions in children and young people presenting at a drop-in mental health centre in the reception area of a paediatric hospital. METHODS: 186 participants attending a transdiagnostic mental health drop-in centre were allocated to assessment and psychological intervention based on a clinical decision-making algorithm. Interventions included signposting, guided self-help based on a modular psychological treatment and referral to the hospital's paediatric psychology service. The primary transdiagnostic mental health outcome measure was the parent-reported Strengths and Difficulties Questionnaire (SDQ), which was given at baseline and 6 months post-baseline. FINDINGS: There was a significant positive impact of attending the drop-in mental health centre on the SDQ (Cohen's d=0.22) and on the secondary outcome measure of Paediatric Quality of life (Cohen's d=0.55). CONCLUSIONS: A mental health drop-in centre offering brief, transdiagnostic assessment and treatment may reduce emotional and behavioural symptoms and improve quality of life in children and young people with mental health needs in the context of long-term physical conditions. A randomised controlled trial to investigate the specificity of any effects is warranted. CLINICAL IMPLICATIONS: Drop-in centres for mental health needs may increase access and have beneficial effects for children and young people with physical conditions

Evaluation of a mental health drop-in centre offering brief transdiagnostic psychological assessment and treatment for children and adolescents with long-term physical conditions and their families: a single-arm, open, non-randomised trial

BACKGROUND: Children and young people with long-term physical conditions have significantly elevated mental health needs. Transdiagnostic, brief psychological interventions have the potential to increase access to evidence-based psychological treatments for patients who attend health services primarily for physical health needs. OBJECTIVE: A non-randomised study was conducted to assess the impact of brief, transdiagnostic psychological interventions in children and young people presenting at a drop-in mental health centre in the reception area of a paediatric hospital. METHODS: 186 participants attending a transdiagnostic mental health drop-in centre were allocated to assessment and psychological intervention based on a clinical decision-making algorithm. Interventions included signposting, guided self-help based on a modular psychological treatment and referral to the hospital's paediatric psychology service. The primary transdiagnostic mental health outcome measure was the parent-reported Strengths and Difficulties Questionnaire (SDQ), which was given at baseline and 6 months post-baseline. FINDINGS: There was a significant positive impact of attending the drop-in mental health centre on the SDQ (Cohen's d=0.22) and on the secondary outcome measure of Paediatric Quality of life (Cohen's d=0.55). CONCLUSIONS: A mental health drop-in centre offering brief, transdiagnostic assessment and treatment may reduce emotional and behavioural symptoms and improve quality of life in children and young people with mental health needs in the context of long-term physical conditions. A randomised controlled trial to investigate the specificity of any effects is warranted. CLINICAL IMPLICATIONS: Drop-in centres for mental health needs may increase access and have beneficial effects for children and young people with physical conditions