How HIV Outmaneuvers the Immune System
T cells and antibody-producing B cells carry out immune defense against specific pathogens such as viruses. Antibodies and T cell receptors are highly diverse molecules that can recognize millions of different molecules. Upon encounter of a foreign antigen (such as a molecule from the surface of a virus), T cells and B cells whose receptors match that particular antigen expand dramatically, providing the immune system with a large number of very specific defenders. After an attack is fought off, the overall numbers of specific T and B cells go down again, but a few of them become long-lived so-called "memory cells" that ensure a quick re-mobilization should the same type of attacker strike again.
T cells consist of two major groups: CD4-positive T helper cells (who help other immune cells in mounting an effective response) and CD8-positive killer T cells. HIV infects and destroys CD4-positive cells, leaving patients with a crippled immune system. Throughout the course of HIV disease, however, patients have high levels of HIV-specific killer T cells. Early after initial infection, these cells are able to effectively kill the virus and reduce viral load. On the other hand, during the later stage of disease killer T cells, while still present, seem no longer able to control the virus. In an article in the November 4 issue of the Journal of Clinical Investigation, Premlata Shankar and colleagues from the Center for Blood Research at Harvard Medical School suggest why this might be the case.
The researchers compared killer T cells from HIV infected asymptomic individuals with those from symptomatic AIDS patients. They examined the killer cells' ability to eliminate target cells infected with laboratory strains of HIV on one hand, and with autologous virus (isolated from the patient) on the other. What they found is that killer T cells from asymptomatic individuals can recognize and kill both types of target cells. In contrast, the killer T cells from symptomatic patients, while still able to recognize and eliminate the laboratory strain targets, no longer killed target cells that were infected with their own, autologous, virus. This is likely due to the virus' propensity to mutate and the in inability of the patient's weakened immune system to keep up with the changing virus.
These results demonstrate that the high number of HIV-specific killer T cells found in AIDS patients are remnants of what used to be an effective response early after infection but no longer recognize the mutated autologous virus. Moreover, these findings reveal that conventional assays to measure killer T cell responses in HIV patients--which focus on responses to laboratory strains--do not accurately reflect but overestimate the response to the patient's autologous virus.
CONTACT:
Premlata Shankar
Harvard Medical School
The Center for Blood Research
800 Huntington Avenue
Boston, MA 02115
USA
PHONE: 617-278-3476
FAX: 617-278-3403
E-mail: shankar@cbr.med.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/16028.pdf
Feeding Your Fat
The growing prevalence of obesity in western societies represents a critical public health concern to millions of people, yet the factors controlling the buildup of fat within our bodies are not completely understood. The involuntary functions of organs such as the heart, stomach and intestines are regulated by the autonomic nervous system. This system is divided into two parts - the sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS). The SNS controls our body's reactions during "fight or flight" situations where heart rate, blood pressure, and energy usage are increased. The primary source of stored energy in mammals are fat deposits and if energy needs cannot be met during "fight or flight" situations, signals sent from the brain via the SNS to fat cells – a process known as SNS innervation - induces the breakdown of fat and the release of extra fuel. On the other hand, the PSNS controls our body during "rest and digest" situations where the body is relaxed and digestion is increased. While it has been demonstrated that dual SNS and PSNS innervation exists in most organs, no such innervation by the PSNS has been demonstrated for fat cells. If present, PSNS innervation may begin to explain the complex mechanisms underlying the buildup of fatty tissue.
A study reported in the November 4 issue of the Journal of Clinical Investigation (JCI) by Felix Kreier and colleagues from the Netherlands Institute for Brain Research in Amsterdam revealed, for the first time, that PSNS innervation of fatty tissue does indeed occur. The authors removed nerves from the sympathetic branch of the nervous system of rats and injected multiple abdominal fat compartments with molecular tagged pseudorabies virus. The replication of viral particles resulted in infections occurring only along the chain of functionally–connected neurons of the PSNS from the fatty tissue to the brain. "Before this work, there was little or no evidence for the PSNS innervation of white adipose tissue" noted Timothy Bartness from the Department of Biology and Center for Behavioral Neuroscience at Georgia State University, Atlanta, in his accompanying Commentary in the JCI. The authors also demonstrated that individual neurons are specialized to control one fat compartment. Dr. Bartness writes further "this could result in enhanced regional accumulation of lipid with certain pathologies. This expansion of the adipose organ in these areas could lead to several well-known adverse health consequences of enhanced visceral/abdominal adiposity such as type II diabetes, certain cancers and high blood pressure." However more work is necessary to reveal whether the nerves described participate in naturally-occurring lipid accumulation, or alternatively are associated with disease-related obesity states.
CONTACT:
Felix Kreier / Ruud M. Buijs
Netherlands Institute for Brain Research
Meibergdreef 33
1105 AZ Amsterdam ZO
Netherlands
PHONE: 31-20-5665500
FAX: 31-20-6961006
E-mail: f.kreier@nih.knaw.nl
View the PDF of this article at: https://www.the-jci.org/press/15736.pdf
ACCOMPANYING COMMENTARY:
Dual innervation of white adipose tissue: some evidence for parasympathetic
nervous system involvement
CONTACT:
Timothy J. Bartness
Department of Biology, MSC 8L0389
Georgia State University
33 Gilmer Street SE, Unit 8
Atlanta, Georgia 30303-3088
USA
PHONE: 404-651-266
FAX: 404-651-2509
E-mail: bartness@gsu.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17047.pdf
Dispersin' Escherichia coli all over the gut
Enteroaggregative Escherichia coli (EAEC) is an emerging pathogen that causes endemic and epidemic diarrhea in developing and industrialized countries. The bacteria stick to the surface of the cells lining the gut and release specific toxins that cause the cells to "open the floodgates" and dramatically increase secretion of electrolytes and water into the gut lumen. EAEC form a thick biofilm on the gut surface that is thought to mediate their persistence and ability to cause disease.
A report in the November 4 issue of the Journal of Clinical Investigation now sheds light on how this protective film might be formed. James Nataro and colleagues of the University of Maryland School of Medicine were searching for proteins that contribute to EAEC's success as a human pathogen as well as those that provoke a robust immune response and might serve as vaccines. One of their discoveries was a molecule that they called 'dispersin' to reflect its ability to promote dispersal of the bacteria on surfaces. Dispersin coats the outside of the EAEC bacteria and seems to help them to penetrate the gut mucous layer and make contact with the underlying intestinal cells. In addition, it may help to spread the bacteria across the gut surface and to form the characteristic biofilm.
EAEC is a rapidly emerging pathogen, but vaccine development is in its earliest stages. Dispersin's position on the bacterial surface (where it is accessible to immune cells) and its presence in the vast majority of EAEC strains make it a potential candidate for vaccine development. Findings by Nataro and colleagues that dispersin can provoke a strong immune response in EAEC-challenged human volunteers, underline its considerable promise.
CONTACT:
James P. Nataro
Center For Vaccine Development
Depts. of Peds., Microbiol., & Immunol.
Univ. of Maryland School Of Medicine
685 W. Baltimore Street
Baltimore, MD 21201
USA
PHONE: 410-706-5328
FAX: 410-706-6205
E-mail: jnataro@medicine.umaryland.edu
View the PDF of this article at: https://www.the-jci.org/press/16172.pdf
Online First
The mouse mahoganoid coat color mutation disrupts a novel C3HC4 RING domain protein
CONTACT:
Rudy L. Leibel
Columbia University
Russ Berrie Pavilion
Room 620
1150 St. Nicholas Ave.
New York, NY 10032
USA
Phone 1: 212-851-5257
Phone 2: 212-751-6794
Fax 1: 212-851-5306
E-mail: rl232@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/16131.pdf
Table of Contents
P311 induces a TGF-b1-independent, nonfibrogenic myofibroblast phenotype
Myofibroblasts are contractile cells whose phenotype lies between fibroblasts and smooth muscle cells. They participate in wound healing and chronic fibrosis and are thought to derive from local fibroblasts in response to TGF-beta signaling. Screening for genes that were upregulated during smooth muscle myogenesis, Lucia Schuger and colleagues identified p311, encoding a protein without functional domains suggested by sequence homology. They now report (pages 1349-1358) that forced P311 expression transformed fibroblasts into myofibroblasts in vitro, and that its expression in vivo during human wound healing is consistent with a proposed causative role. Surprisingly, P311 inhibited TGF-beta signaling and collagen expression, suggesting that it exerts anti-fibrotic effects. These results raise the possibility that manipulation of P311 and its downstream effectors might facilitate wound healing and reduce scarring.
CONTACT:
Lucia Schuger
Wayne State University Medical School
Associate Professor of Pathology
9374 Gordon H Scott Hall
540 East Canfield
Detroit, MI 48201
USA
Phone 1: 313-577-5651
Fax 1: 313-577-0057
E-mail: lschuger@med.wayne.edu
View the PDF of this article at: https://www.the-jci.org/press/15614.pdf
Manipulation of lymphoid microenvironments in nonhuman primates by an inhibitor of the lymphotoxin pathway
The lymphotoxin (LT) system plays a key role in the development and maintenance of lymphoid tissues. In mice, the interruption of lymphotoxin-beta receptor (LTbR) signaling results in the collapse of several lymphoid microenvironments including follicular dendritic cells (FDCs) that trap immune complexes (ICs) on their dendritic surface and subsequently serve as long-term antigen reservoirs. This IC trapping may be exploited by pathogens such as HIV that can persist in FDC networks during treatment, and may also aid the progression of autoimmune diseases. Jeffrey Browning and colleagues (pages 1359-1369) examined the effects of perturbing FDC networks in nonhuman primates. In cynomolgus monkeys treated with the decoy receptor LTbR-Ig, splenic FDC networks collapsed and prohibited IC trapping in lymphoid tissues, whereas the Ab response to neo-antigen challenge was unaffected. Three months after cessation of treatment, FDC networks reappeared in the germinal centers, suggesting that FDC disruption may represent a candidate for the transient alteration of human immune function during disease.
CONTACT:
Jeffrey L. Browning
Biogen Incorporated
12 Cambridge Center
Cambridge, MA 02142
USA
Phone 1: 617-679-3312
Fax 1: 617-679-2304
E-mail: jeff_browning@biogen.com
View the PDF of this article at: https://www.the-jci.org/press/15975.pdf
In vivo regulation of plasminogen function by plasma carboxypeptidase B
CONTACT:
Edward Plow
Cleveland Clinic Foundation
Department of Molecular Cardiology
9500 Euclid Avenue
NB50
Cleveland, Ohio 44195
USA
Phone 1: 216 445 8200
Fax 1: 216 445 8204
E-mail: plowe@ccf.org
View the PDF of this article at: https://www.the-jci.org/press/15082.pdf
Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo
CONTACT:
Gert Fricker
University of Heidelberg
Institut fur Pharmazeutische Technologie und Biopharmazie
Im Neuenheimer Feld 366
69120 Heidelberg,
GERMANY
Phone 1: 49-6221-548-336
Fax 1: 49-6221-545-971
E-mail: jw3@ix.urz.uni-heidelberg.de
View the PDF of this article at: https://www.the-jci.org/press/15451.pdf
Impaired glucose phosphorylation and transport in skeletal muscle cause insulin resistance in HIV-1-infected patients with lipodystrophy
CONTACT:
Georg M. N. Behrens
The Walter and Eliza Hall Institute of Medical Research
Immunology Division
Post Office of The Royal Melbourne Hospital
Parkville 3050, Victoria
AUSTRALIA
Phone 1: 613-9345-2482
Fax 1: 613-9347-0852
E-mail: behrens@wehi.edu.au
View the PDF of this article at: https://www.the-jci.org/press/15626.pdf
Impaired renal Na+ retention in the sgk1-knockout mouse
CONTACT:
Dietmar Kuhl
Free University Berlin
Institute of Molecular Neurobiology
Department of Biology-Chemistry-Pharmacy
Takustr. 6
D-14195 Berlin, UNK
GERMANY
Phone 1: 49-30-83856940
Fax 1: 49-30-83856943
E-mail: kuhl@chemie.fu-berlin.de
ACCOMPANYING COMMENTARY:
Sgk: an old enzyme revisited
CONTACT:
Nicolette Farman
INSERM U 246
Faculte de Medecine X. Bichat
BP 416
758707 Paris Cedex 18,
FRANCE
Phone 1: 33 1 44 85 63 23
Fax 1: +33 1 42 29 16 44
E-mail: farman@bichat.inserm.fr
View the PDF of this article at: https://www.the-jci.org/press/15696.pdf
View the PDF of this commentary at: https://www.the-jci.org/press/17064.pdf
Allergen-specific CD8+ T cells and atopic disease
CONTACT:
Graham S. Ogg
Weatherall Institute of Molecular Medicine
Institite of Molecular Medicine
Immunology Group
Oxford, OX3 9DS
GREAT BRITAIN
Phone 1: 44 1865 222334
Fax 1: 44-1865-222-502
E-mail: gogg@molbiol.ox.ac.uk
View the PDF of this article at: https://www.the-jci.org/press/15753.pdf
The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta
CONTACT:
Frank Rauch
Shriners Hospital
1529 Cedar Avenue
Montreal, PQ H3G 1A6
CANADA
Phone 1: (514)-282-7193
Fax 1: (514)-842-5581
E-mail: frauch@shriners.mcgill.ca
View the PDF of this article at: https://www.the-jci.org/press/15952.pdf
ACCOMPANYING COMMENTARY:
Modeling the benefits of pamidronate in children with osteogenesis
imperfecta
CONTACT:
Robert Lindsay
Helen Hayes Hospital
Reg Bone Ctr
Route 9W
West Haverstraw, NY 10993
USA
Phone 1: 845-786-4494
Fax 1: 845-786-4878
E-mail: lindsayr@helenhayeshosp.org
View the PDF of this commentary at: https://www.the-jci.org/press/17051.pdf
Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis
CONTACT:
Kentaro Hanada
National Institute of Infectious Diseases
Department of Biochemistry and Cell Biology
1-23-1 Toyama
Shinjuku-ku
Tokyo 162-8640,
JAPAN
Phone 1: 813-5285-1111
Fax 1: 813-5285-1157
E-mail: hanak@nih.go.jp
View the PDF of this article at: https://www.the-jci.org/press/16450.pdf
Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection
CONTACT:
Edward M. Medof
Case Western Reserve University School of Medicine
Institute of Pathology
2085 Adelbert Road
Room 301
Cleveland, OH 44106
USA
Phone 1: 216 368 5434
Fax 1: 216 368 0495
E-mail: mxm16@po.cwru.edu
Current review assignments
View the PDF of this article at: https://www.the-jci.org/press/16086.pdf
Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome
CONTACT:
Robert S. Kass
Department of Pharmacology
Columbia University College of Physicians and Surgeons
630 W. 168th St.
New York, NY 10032
USA
Phone: 212-305-7444
Fax: 212-342-2703
E-mail: rsk20@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/15928.pdf
Journal
Journal of Clinical Investigation