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Current Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 7, Number 2, March 2007
Contents
Designing Recombinant Vaccines with Viral Properties:
A Rational Approach to More Effective Vaccines Pp.
143-155
Gary T. Jennings and Martin F. Bachmann
[Abstract]
Hematopoietic Cytokines – on the Verge of Conquering
Neurology Pp. 157-170
Lars Tönges, Johannes C.M. Schlachetzki, Jochen H.
Weishaupt and Mathias Bähr
[Abstract]
Mechanisms of CD4 Downregulation by the Nef and Vpu
Proteins of Primate Immunodeficiency Viruses Pp.
171-184
O. Wolf Lindwasser, Rittik Chaudhuri and Juan S. Bonifacino
[Abstract]
Molecular Mechanisms of Resistance to Antiviral Therapy
in Patients with Chronic Hepatitis B Pp. 185-197
He-Jun Yuan and William M. Lee
[Abstract]
Enzymes in the Conversion of Cholesterol into Bile
Acids Pp. 199-218
Maria Norlin and Kjell Wikvall
[Abstract]
ICAM-1 in Acute Myocardial Infarction: A Potential
Therapeutic Target Pp. 219-227
Victoria Benson, Aisling Clare McMahon and Harry Claude
Lowe
[Abstract]
Abstracts
[Back to top]
Designing Recombinant Vaccines with Viral
Properties: A Rational Approach to More Effective Vaccines
Gary T. Jennings and Martin F. Bachmann
One of the great demands and challenges for vaccination is
to successfully target the pathogens responsible for much
of mankind's chronic disease burden including: AIDS, infectious
hepatitis, tuberculosis and malaria. Another is realizing
the potential of therapeutic immunization to cure diseases
such as cancer, allergy and inflammatory autoimmunity. To
achieve these objectives, the fundamental insights gained
from immunology, genomics, molecular-cellular biology and
vaccinology must be implemented in order to develop more effective,
better defined and safer vaccines. As an illustrative example
of this we examine the key features of viruses that are known
to be responsible for eliciting superb host immune responses.
These insights have formed a basis for understanding the effectiveness
of existing vaccines and provide a framework for designing
and developing new vaccines better able to meet pressing unmet
medical needs. The key immunogenic properties of viruses that
are understood to date and are currently being applied include:
their particulate nature, their highly repetitive and ordered
structures, their ability to induce innate immunity with consequent
conditioning of adaptive responses and the kinetics and distribution
of viral antigens during infection. Vaccines and vaccine-formulations
recently registered for use in humans already incorporate
some of these elements. Of great anticipation is the progress
of the next-generation vaccines now advancing through the
various stages of research and development. Vaccines which,
by way of rational design, incorporate viral properties to
induce tailored responses and thus have the potential to provide
safer and more effective prophylaxis and therapies.
[Back to top]
Hematopoietic Cytokines – on the Verge of Conquering
Neurology
Lars Tönges, Johannes C.M. Schlachetzki, Jochen H.
Weishaupt and Mathias Bähr
Two hematopoietic cytokines are currently gaining increasing
attention within neurological research. Erythropoietin (EPO)
and granulocyte-colony stimulating factor (G-CSF) have long
been known for their ability to induce the proliferation of
certain populations of hematopoietic lineage cells. However,
it has recently been found that EPO, G-CSF, and their respective
receptors are also expressed in the human central nervous
system (CNS) and may be an important part of the brain’s
endogenous system of protection. Both hematopoietic cytokines
have been shown to have neuroprotective potential in a variety
of animal disease models both in vitro and in
vivo, through the inhibition of apoptosis, induction
of angiogenesis, exertion of anti-inflammatory and neurotrophic
effects, as well as by the enhancement of neurogenesis. EPO
and G-CSF have been extensively studied in the context of
hematological disorders and have recently been successfully
applied in the first clinical trials in stroke patients. Intravenous
high-dose EPO therapy was associated with an improvement in
the clinical outcome and preclinical studies with intravenous
high-dose G-CSF therapy have clearly shown that it has considerable
neuroprotective potential in the acute, as well as in the
chronic phase of stroke. In this review, the current knowledge
of the neuroprotective mechanisms of EPO and G-CSF is summarized
with regard to in vitro and in vivo data.
Focus is placed on the role of EPO in neurological disease
models with an emphasis on its influence on functional outcome.
New experimental results are assessed in detail and correlated
with the findings of recent clinical studies.
[Back to top]
Mechanisms of CD4 Downregulation by the Nef and Vpu
Proteins of Primate Immunodeficiency Viruses
O. Wolf Lindwasser, Rittik Chaudhuri and Juan S. Bonifacino
Human immunodeficiency virus type 1 (HIV-1), human immunodeficiency
virus type 2 (HIV-2), and simian immunodeficiency virus (SIV)
are the etiological agents of acquired immunodeficiency syndrome
(AIDS) in humans and a related disease in non-human primates.
These viruses infect T cells and macrophages that express
the surface glycoprotein, CD4, because this glycoprotein acts
as a co-receptor for incoming virus particles. Once infection
has occurred, however, the presence of CD4 poses problems
for the virus life cycle, including the possibility of superinfection,
premature binding of CD4 to nascent virus particles, and inhibition
of virus release. Accordingly, primate immunodeficiency viruses
have evolved at least two distinct mechanisms, mediated by
the Nef and Vpu viral proteins, to “downregulate”
CD4 in the host cells. Nef and Vpu are mainly expressed early
and late, respectively, in the viral life cycle, ensuring
continuous removal of CD4. Nef links mature CD4 to components
of clathrin-dependent trafficking pathways at the plasma membrane,
and perhaps in intracellular compartments, leading to internalization
and delivery of CD4 to lysosomes for degradation. Vpu, on
the other hand, interacts with newly-synthesized CD4 in the
endoplasmic reticulum, linking CD4 to the SCF ubiquitin ligase
and facilitating the entry of CD4 into the endoplasmic-reticulum-associated
degradation pathway. These two mechanisms lead to a dramatic
reduction of CD4 expression in infected cells and are essential
for efficient virus replication and disease progression.
[Back to top]
Molecular Mechanisms of Resistance to Antiviral Therapy
in Patients with Chronic Hepatitis B
He-Jun Yuan and William M. Lee
Similar to the human immunodeficiency virus (HIV), the hepatitis
B virus (HBV) replicates via reverse transcription,
in this case, within infected hepatocytes. Substantial advances
have been achieved in the past ten years in developing and
utilizing nucleoside/nucleotide analog drugs to inhibit HBV
replication. Most are chain terminators that interfere with
one or more steps in the replication cycle. Four of them (lamivudine,
adefovir dipivoxil, entecavir, and telbivudine), have been
approved by the United States Food and Drug Administration
(FDA) for the treatment of chronic hepatitis B (CHB). In clinical
trials of HBeAg positive and negative CHB patients, 48-52
week of treatment with these drugs can induce a 4-7 log decrease
of HBV viremia and histological improvement. Long-term suppression
of active HBV replication has been found to be associated
with decreased inflammation, reversal of liver fibrosis and
a lower incidence of hepatocellular carcinoma. However, permanent
clearance of HBV is rarely achieved with current available
antiviral agents, maintenance therapy being required for continuous
suppression of HBV replication. In patients on continuous
therapy, drug resistant mutations develop with all four drugs.
Combination therapy with different nucleos(t)ide analog drugs
or nucleos(t)ide drugs and pegylated interferon needs further
clinical study. Newer promising nucleotide analog drugs with
more potent antiviral efficacy are also under development.
[Back to top]
Enzymes in the Conversion of Cholesterol into Bile
Acids
Maria Norlin and Kjell Wikvall
This article aims to give an overview on the characterization,
properties and regulation of enzymes, particularly the cytochrome
(CYP) P450 enzymes, in the formation of bile acids from cholesterol.
Bile acids are biologically active molecules that promote
absorption of dietary lipids in the intestine and stimulate
biliary excretion of cholesterol. Bile acids and oxysterols,
formed from cholesterol, act as ligands to nuclear receptors
regulating the expression of important genes in cholesterol
homeostasis. Thus, the bioactivation of cholesterol into bile
acids is crucial for regulation of cholesterol homeostasis.
The primary human bile acids, cholic acid and chenodeoxycholic
acid, are formed from cholesterol via several pathways
involving many different enzymes. Many of these enzymes are
cytochrome P450 (CYP) enzymes, introducing a hydroxyl group
in the molecule. The “classic” pathway of bile
acid formation starts with a 7α-hydroxylation
of cholesterol by CYP7A1 in the liver. The “acidic”
pathway starts with a hepatic or extrahepatic 27-hydroxylation
by CYP27A1. There also exist some quantitatively minor pathways
which may be of importance under certain conditions. Formation
of cholic acid requires insertion of a 12α-hydroxyl
group performed by CYP8B1. Oxysterols are precursors to bile
acids, participate in cholesterol transport and are known
to affect the expression of several genes in cholesterol homeostasis.
Enzymes with capacity to form and metabolize oxysterols are
present in liver and extrahepatic tissues. The enzymes, nuclear
receptors and transcription factors involved in bile acid
biosynthesis are potential pharmaceutical targets for the
development of new drugs to control hypercholesterolemia and
to prevent atherosclerosis and other diseases related to disturbed
cholesterol homeostasis. The review will also discuss some
inborn errors of bile acid biosynthesis and the recently acquired
knowledge on the genetic defects underlying these diseases.
[Back to top]
ICAM-1 in Acute Myocardial Infarction: A Potential
Therapeutic Target
Victoria Benson, Aisling Clare McMahon and Harry Claude
Lowe
Current treatments for AMI centre on prompt restoration
of epicardial coronary blood flow. Despite improvements, AMI
is still associated with significant morbidity and mortality.
Novel approaches are therefore keenly sought.
Intercellular adhesion molecule-1 (ICAM-1, CD54) is a member
of the immunoglobulin superfamily. It is implicated in neutrophil
and monocyte-endothelial cell adhesion, processes contributing
to myocardial neutrophil infiltration and microvascular coronary
slow flow, both viewed as important to the pathophysiologic
responses in AMI. ICAM-1 would therefore appear an important
potential therapeutic target in this context, and is the subject
of this review.
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