Volume 18 Issue 9, September 2012

Volume 18 Issue 9

Antiretroviral therapy has transformed outcomes for HIV-1–infected individuals. In this issue, Rosenbloom et al. (p 1378) model the dynamics of different antiretroviral drugs, shedding new light on the distinct patterns of viral resistance observed clinically. The editorial also reflects on the future of HIV therapy with the current push toward achieving a cure. Cover image credit: Karen Vanderbilt

Editorial

  • Editorial |

    This summer, researchers launched a strategy to accelerate finding a cure for HIV. The effort aims to revolutionize treatment of the infection, but the inherent risks require that regulators ensure a measured approach.

News

Correction

News

Q&A

  • Q&A |

    By 2014, the UK will be changing the way it regulates the price it pays for medicines. The government has embraced an idea known as value-based pricing (VBP), with negotiations on how the system will work due to begin this month. One of the most influential thinkers on the UK’s proposed system is health economist Mark Sculpher, director of the Programme on Economic Evaluation and Health Technology Assessment at the University of York. Kate Ravilious met with Sculpher to discuss the value of VBP.

News in Brief

News Feature

  • News Feature |

    The idea of using bacteria-fighting viruses as a weapon against hard-to-treat infections is making a surprising comeback, but with a twist on how it has been attempted for nearly a century. Researchers and companies are now tweaking and deconstructing these bacteria killers in an effort to develop a new arsenal against antibiotic-resistant superbugs—one with more potency and a better likelihood of regulatory approval. Lauren Gravitz reports.

    • Lauren Gravitz

Opinion

  • Opinion |

    Doctors and regulatory agencies rely on meta-analyses when setting clinical guidelines and making decisions about drugs. However, as the number of these analyses increases, it's clear that many of them lack robust evidence from randomized trials, which may lead to the adoption of treatment modalities of ambiguous value. Without a more disciplined approach requiring a reasonable minimum amount of data, meta-analyses could lose credibility.

    • Peter Humaidan
    •  & Nikolaos P Polyzos

Book Review

Correspondence

News & Views

  • News & Views |

    Hepatic fibrosis results from chronic liver injury due to viral infection, metabolic diseases, toxins such as alcohol, or immune attack. Now, a heritable epigenetic determinant of fibrosis has been uncovered, providing evidence that sperm from male rats with liver injury confers reduced fibrosis in their male offspring ( pages 1369– 1377 ).

    • Scott L Friedman
  • News & Views |

    A better understanding of mechanisms involved in regulation of drug sensitivity is crucial for improved cancer treatment. New studies show that cells of the tumor microenvironment modulate the response of cancer cells to chemotherapy and targeted therapies through production of secreted factors ( pages 1359–1368 ).

    • Arne Östman
  • News & Views |

    Unraveling the intracellular networks that regulate the self-renewal and differentiation of hematopoietic stem cells (HSCs) is crucial to enhancing the efficacy of these therapeutic transplantable cells. A newly discovered pathway links a leukemia tumor suppressor gene with a nutrient sensor to regulate fatty-acid oxidation (FAO) and stem cell division—information with the potential for modulating hematopoiesis for clinical advantage ( pages 1350–1358 ).

    • Hal E Broxmeyer
    •  & Charlie Mantel
  • News & Views |

    Neutrophils release extracellular DNA traps (NETs) to capture and kill pathogens. A recent study shows that live neutrophils are simultaneously able to form NETs while crawling and phagocytosing and can even combat bacteria after loss of their nuclear DNA ( pages 1386–1393 ).

    • Andreas Peschel
    •  & Dominik Hartl
  • News & Views |

    T cells responding to tumor cells and chronic viral pathogens are ineffective because their function is suppressed by inhibitory receptors such as Tim-3. New work identifies the first component of the Tim-3 inhibitory signaling pathway in T cells ( pages 1394–1400 ).

    • W Nicholas Haining
  • News & Views |

    Complement is intricately involved in inflammatory processes, yet the mechanisms that modulate the actions of its key mediator C5a are poorly understood. A new study uncovers a molecular partnership between three neutrophil receptors in the recognition of differentially glycated immune complexes and sheds light on regulatory processes in autoimmune and inflammatory disorders ( pages 1401–1406 ).

    • Daniel Ricklin
    • , Edimara S Reis
    •  & John D Lambris

Community Corner

Between Bedside and Bench

  • Between Bedside and Bench |

    Formation of plaques in artery walls, or atherogenesis, is known to lead to cardiovascular disease risk and heart disease. Low-density lipoproteins (LDLs), which deliver cholesterol to inflammatory cells in blood vessels, are linked to disease, which is commonly managed using cholesterol-lowering therapies. Whether increasing levels of high-density lipoproteins (HDLs), which remove cholesterol from the circulation, can be cardioprotective has not been clear, despite early clinical studies showing evidence for a positive effect in cardiovascular disease. In 'Bench to Bedside', Daniel J. Rader and Alan R. Tall discuss how the field should focus on promoting reverse cholesterol transport that would result in cholesterol efflux from macrophages to biliary excretion rather than simply trying to increase HDL cholesterol levels. Understanding how different molecular mechanisms operate in this 'HDL flux hypothesis' will uncover ways to develop HDL-targeted therapeutics that will protect from cardiovascular and heart disease. In 'Bedside to Bench', Jay W. Heinecke peruses clinical studies to propose better and simpler ways to measure reverse cholesterol transport in the clinic. Genetic alterations and factors involved in HDL functionality may be useful for quantifying HDL function and finding effective drugs to lower cardiovascular disease risk.

    • Daniel J Rader
    •  & Alan R Tall

Research Highlights

Article

  • Article |

    Keisuke Ito et al. uncover a new pathway regulating hematopoietic stem cell maintenance and function. In this pathway, the promyelocytic leukemia protein (PML) regulates the activity of the PPAR-δ nuclear hormone receptor and, thereby, fatty acid oxidation, such that PPAR-δ activators have the potential of improving stem cell function. Intriguingly, this pathway controls the cell fate of dividing stem cells.

    • Keisuke Ito
    • , Arkaitz Carracedo
    • , Dror Weiss
    • , Fumio Arai
    • , Ugo Ala
    • , David E Avigan
    • , Zachary T Schafer
    • , Ronald M Evans
    • , Toshio Suda
    • , Chih-Hao Lee
    •  & Pier Paolo Pandolfi
  • Article |

    Responses to anticancer therapy are hampered by several factors, and Peter S. Nelson and colleagues here identify a protective effect of the tumor microenvironment. After cytotoxic chemotherapy, inflammatory NF-κB signaling activates the secretion of WNT16B, which acts on epithelial cells, promoting their survival and fostering tumor growth in vivo. This pathway is also active in human tumors treated with chemotherapy and illustrates the potential caveats of cyclical therapy and the need to overcome environmental protection to successfully eliminate tumors.

    • Yu Sun
    • , Judith Campisi
    • , Celestia Higano
    • , Tomasz M Beer
    • , Peggy Porter
    • , Ilsa Coleman
    • , Lawrence True
    •  & Peter S Nelson
  • Article |

    Derek Mann and his colleagues have found that experimental induction of liver fibrosis in male rats results in an epigenetic modification of the chromatin in their sperm such that their offspring have a more mild wound-healing response to hepatic fibrogenic insults. The mechanism responsible for this phenomenon is not clear, but it seems to involve a yet unidentified soluble factor released by myofibroblasts that act on either the germ cells or mature sperm.

    • Müjdat Zeybel
    • , Timothy Hardy
    • , Yi K Wong
    • , John C Mathers
    • , Christopher R Fox
    • , Agata Gackowska
    • , Fiona Oakley
    • , Alastair D Burt
    • , Caroline L Wilson
    • , Quentin M Anstee
    • , Matt J Barter
    • , Steven Masson
    • , Ahmed M Elsharkawy
    • , Derek A Mann
    •  & Jelena Mann
  • Article |

    Highly active antiretroviral therapy is crucial to controlling the progression of HIV infection. Therapy failure is often—but not always—attributed to resistance mutations in the HIV-1–encoded protein targets. Here Rosenbloom et al. use mathematical modeling to explain the distinct patterns of resistance found with different classes of antiretroviral drugs and predict specific single-pill combination therapies that might prevent resistance even in the setting of poor patient adherence.

    • Daniel I S Rosenbloom
    • , Alison L Hill
    • , S Alireza Rabi
    • , Robert F Siliciano
    •  & Martin A Nowak
  • Article |

    Bacteria can be trapped by neutrophil extracellular traps (NETs) in vitro, but their relevance in vivo is uncertain, in part because NETs are thought to be released by dying neutrophils, thereby eliminating the other antimicrobial functions of these cells. Paul Kubes and his colleagues report in this issue that NET release need not kill neutrophils and that NETosis can by dynamically imaged in vivo.

    • Bryan G Yipp
    • , Björn Petri
    • , Davide Salina
    • , Craig N Jenne
    • , Brittney N V Scott
    • , Lori D Zbytnuik
    • , Keir Pittman
    • , Muhammad Asaduzzaman
    • , Kaiyu Wu
    • , H Christopher Meijndert
    • , Stephen E Malawista
    • , Anne de Boisfleury Chevance
    • , Kunyan Zhang
    • , John Conly
    •  & Paul Kubes
  • Article |

    T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells and suppresses T helper type 1 (TH1) responses. Vijay Kuchroo and his colleagues show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds intracellularly to Tim-3 and represses its function. Bat3 knockdown suppresses the development of experimental autoimmune encephalomyelitis and induces an exhaustion-like phenotype in T cells.

    • Manu Rangachari
    • , Chen Zhu
    • , Kaori Sakuishi
    • , Sheng Xiao
    • , Jozsef Karman
    • , Andrew Chen
    • , Mathieu Angin
    • , Andrew Wakeham
    • , Edward A Greenfield
    • , Raymond A Sobel
    • , Hitoshi Okada
    • , Peter J McKinnon
    • , Tak W Mak
    • , Marylyn M Addo
    • , Ana C Anderson
    •  & Vijay K Kuchroo

Letter

  • Letter |

    Complement components activate and recruit immune cells, promoting host defense and inflammatory disease. Jörg Köhl and his colleagues demonstrate that IgG1 immune complexes inhibit C5a-mediated inflammatory responses and disease. The inhibitory effect of IgG1 immune complexes requires galactosylation of the antibody, binding to the inhibitory IgG receptor FcγRIIB and the association of FcγRIIB with the C-type lectin–like receptor dectin-1.

    • Christian M Karsten
    • , Manoj K Pandey
    • , Julia Figge
    • , Regina Kilchenstein
    • , Philip R Taylor
    • , Marcela Rosas
    • , Jacqueline U McDonald
    • , Selinda J Orr
    • , Markus Berger
    • , Dominique Petzold
    • , Veroniqué Blanchard
    • , André Winkler
    • , Constanze Hess
    • , Delyth M Reid
    • , Irina V Majoul
    • , Richard T Strait
    • , Nathaniel L Harris
    • , Gabriele Köhl
    • , Eva Wex
    • , Ralf Ludwig
    • , Detlef Zillikens
    • , Falk Nimmerjahn
    • , Fred D Finkelman
    • , Gordon D Brown
    • , Marc Ehlers
    •  & Jörg Köhl
  • Letter |

    Infiltration of various immune cell types into the fat tissue and liver has been implicated in obesity-induced insulin resistance. Jerry Olefsky and his colleagues now show that neutrophils are one of the earliest immune cells to arrive in these tissues, that they release the protease neutrophil elastase and that this enzyme degrades IRS-1, a key member of the insulin signaling pathway. These results show that neutrophils contribute to insulin resistance and how they may do so.

    • Saswata Talukdar
    • , Da Young Oh
    • , Gautam Bandyopadhyay
    • , Dongmei Li
    • , Jianfeng Xu
    • , Joanne McNelis
    • , Min Lu
    • , Pingping Li
    • , Qingyun Yan
    • , Yimin Zhu
    • , Jachelle Ofrecio
    • , Michael Lin
    • , Martin B Brenner
    •  & Jerrold M Olefsky
  • Letter |

    Ronald Duman and colleagues report that synapse number is reduced in subjects with major depressive disorder. This is associated with decreased expression of synapse-related genes and increased expression of the transcriptional repressor, GATA1. Expression of GATA1 in prefrontal cortex neurons decreases the expression of synapse-related genes, reduces dendrite branching and produces depressive behavior in a rat model of depression.

    • Hyo Jung Kang
    • , Bhavya Voleti
    • , Tibor Hajszan
    • , Grazyna Rajkowska
    • , Craig A Stockmeier
    • , Pawel Licznerski
    • , Ashley Lepack
    • , Mahesh S Majik
    • , Lak Shin Jeong
    • , Mounira Banasr
    • , Hyeon Son
    •  & Ronald S Duman

    Special:

  • Letter |

    Epha4 is a receptor involved in axonal repulsion. Wim Robberecht and his colleagues report that genetic or pharmacological inhibition of Epha4 is protective in rodent and zebrafish models of amyotrophic lateral sclerosis. In humans, expression of Epha4 inversely correlates with disease onset and survival, and in two patients, mutations in Epha4 are associated with longer survival, suggesting Epha4 may be targeted therapeutically to prevent axonal degeneration.

    • Annelies Van Hoecke
    • , Lies Schoonaert
    • , Robin Lemmens
    • , Mieke Timmers
    • , Kim A Staats
    • , Angela S Laird
    • , Elke Peeters
    • , Thomas Philips
    • , An Goris
    • , Bénédicte Dubois
    • , Peter M Andersen
    • , Ammar Al-Chalabi
    • , Vincent Thijs
    • , Ann M Turnley
    • , Paul W van Vught
    • , Jan H Veldink
    • , Orla Hardiman
    • , Ludo Van Den Bosch
    • , Paloma Gonzalez-Perez
    • , Philip Van Damme
    • , Robert H Brown Jr
    • , Leonard H van den Berg
    •  & Wim Robberecht
  • Letter |

    Ciliopathies are caused by alterations in the development and function of cilia. Now Jeffrey Martens and his colleagues demonstrate anatomic and functional rescue of cilia development in mature, differentiated neurons by adenovirus-mediated restoration of expression of the wild-type protein intraflagellar transport protein 88 (Ift88) and show restoration of olfactory function in a mouse model of ciliopathy. A loss-of-function mutation in IFT88 is also identified in individuals with ciliopathies.

    • Jeremy C McIntyre
    • , Erica E Davis
    • , Ariell Joiner
    • , Corey L Williams
    • , I-Chun Tsai
    • , Paul M Jenkins
    • , Dyke P McEwen
    • , Lian Zhang
    • , John Escobado
    • , Sophie Thomas
    • , Katarzyna Szymanska
    • , Colin A Johnson
    • , Philip L Beales
    • , Eric D Green
    • , James C Mullikin
    • , NISC Comparative Sequencing Program
    • , Aniko Sabo
    • , Donna M Muzny
    • , Richard A Gibbs
    • , Tania Attié-Bitach
    • , Bradley K Yoder
    • , Randall R Reed
    • , Nicholas Katsanis
    •  & Jeffrey R Martens
  • Letter |

    The mineralocorticoid receptor, targeted by drugs commonly used to treat hypertension, is generally thought to contribute to hypertension by altering kidney function. Using mice lacking the mineralocorticoid receptor specifically in smooth muscle cells, Iris Jaffe and her colleagues show that it also controls many aspects of vascular aging, including blood vessel tone, and that these vascular effects contribute to the mineralocorticoid receptor's prohypertensive actions.

    • Amy McCurley
    • , Paulo W Pires
    • , Shawn B Bender
    • , Mark Aronovitz
    • , Michelle J Zhao
    • , Daniel Metzger
    • , Pierre Chambon
    • , Michael A Hill
    • , Anne M Dorrance
    • , Michael E Mendelsohn
    •  & Iris Z Jaffe

Technical Report

  • Technical Report |

    Using the semiconductor synthesis technology of maskless photolithography on microprocessor-grade silicon wafers, Jordan Price and colleagues synthesized microarrays containing every possible overlapping peptide in a linear sequence covering the N terminus of human histone H2B, including post-translational modifications. They demonstrated use of the 'on silico' peptide microarrays for the high-resolution mapping (at the single amino acid level) of epitopes targeted by commercially available H2B-specific antibodies and also by autoantibodies in samples from individuals with systemic lupus erythematosus.

    • Jordan V Price
    • , Stephanie Tangsombatvisit
    • , Guangyu Xu
    • , Jiangtao Yu
    • , Dan Levy
    • , Emily C Baechler
    • , Or Gozani
    • , Madoo Varma
    • , Paul J Utz
    •  & Chih Long Liu

Erratum

  • Erratum |

    • Koji Fujita
    • , Makiko Iwasaki
    • , Hiroki Ochi
    • , Toru Fukuda
    • , Chengshan Ma
    • , Takeshi Miyamoto
    • , Kimitaka Takitani
    • , Takako Negishi-Koga
    • , Satoko Sunamura
    • , Tatsuhiko Kodama
    • , Hiroshi Takayanagi
    • , Hiroshi Tamai
    • , Shigeaki Kato
    • , Hiroyuki Arai
    • , Kenichi Shinomiya
    • , Hiroshi Itoh
    • , Atsushi Okawa
    •  & Shu Takeda

Corrigendum

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