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July 11, 2010)
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11 Jul 2010
Scientists have discovered two potent human antibodies that can stop more than
90 percent of known global HIV strains from infecting human cells in the
laboratory, and have demonstrated how one of these disease-fighting proteins
accomplishes this feat. According to the scientists, these antibodies could be
used to design improved HIV vaccines, or could be further developed to prevent
or treat HIV infection. Moreover, the method used to find these antibodies could
be applied to isolate therapeutic antibodies for other infectious diseases as
well.
"The discovery of these exceptionally broadly neutralizing antibodies to
HIV and the structural analysis that explains how they work are exciting
advances that will accelerate our efforts to find a preventive HIV vaccine for
global use," says Anthony S. Fauci, M.D., director of the National
Institute of Allergy and Infectious Diseases (NIAID), National Institutes of
Health. "In addition, the technique the teams used to find the new
antibodies represents a novel strategy that could be applied to vaccine design
for many other infectious diseases."
Led by a team from the NIAID Vaccine Research Center (VRC), the scientists found
two naturally occurring, powerful antibodies called VRC01 and VRC02 in an
HIV-infected individual's blood. They found the antibodies using a novel
molecular device they developed that homes in on the specific cells that make
antibodies against HIV. The device is an HIV protein that the scientists
modified so it would react only with antibodies specific to the site where the
virus binds to cells it infects.
The scientists found that VRC01 and VRC02 neutralize more HIV strains with
greater overall strength than previously known antibodies to the virus.
The researchers also determined the atomic-level structure of VRC01 when it is
attaching to HIV. This has enabled the team to define how the antibody works and
to precisely locate where it attaches to the virus. With this knowledge, they
have begun to design components of a candidate vaccine that could teach the
human immune system to make antibodies similar to VRC01 that might prevent
infection by the vast majority of HIV strains worldwide.
NIAID scientists Peter D. Kwong, Ph.D., John R. Mascola, M.D., and Gary J. Nabel,
M.D., Ph.D., led the two research teams. A pair of articles about these findings
appears in the online edition of Science.
"We have used our knowledge of the structure of a virus - in this case, the
outer surface of HIV - to refine molecular tools that pinpoint the vulnerable
spot on the virus and guide us to antibodies that attach to this spot, blocking
the virus from infecting cells," explains Dr. Nabel, the VRC director.
Finding individual antibodies that can neutralize HIV strains anywhere in the
world has been difficult because the virus continuously changes its surface
proteins to evade recognition by the immune system. As a consequence of these
changes, an enormous number of HIV variants exist worldwide. Even so, scientists
have identified a few areas on HIV's surface that remain nearly constant across
all variants. One such area, located on the surface spikes used by HIV to attach
to immune system cells and infect them, is called the CD4 binding site. VRC01
and VRC02 block HIV infection by attaching to the CD4 binding site, preventing
the virus from latching onto immune cells.
"The antibodies attach to a virtually unchanging part of the virus, and
this explains why they can neutralize such an extraordinary range of HIV
strains," says Dr. Mascola, the deputy director of the VRC.
With these antibodies in hand, a team led by Dr. Kwong, chief of the structural
biology section at the VRC, determined the atomic-level molecular structure of
VRC01 when attached to the CD4 binding site. They then examined this structure
in light of natural antibody development to ascertain the steps that would be
needed to elicit a VRC01-like antibody through vaccination.
Antibody development begins with the mixing of genes into new combinations
within the immune cells that make antibodies. Examination of the structure of
VRC01 attached to HIV suggested that, from a genetic standpoint, the immune
system likely could produce VRC01 precursors readily. The researchers also
confirmed that VRC01 does not bind to human cells - a characteristic that might
otherwise lead to its elimination during immune development, a natural mechanism
the body employs to prevent autoimmune disease.
In the final stage of antibody development, antibody-producing B cells recognize
specific parts of a pathogen and then mutate, or mature, so the antibody can
bind to the pathogen more firmly. VRC01 precursors do not bind tightly to HIV,
but rather mature extensively into more powerfully neutralizing forms. This
extensive antibody maturation presents a challenge for vaccine design. In their
paper, Dr. Kwong and colleagues explore how this challenge might be addressed by
designing vaccine components that could guide the immune system through this
stepwise maturation process and facilitate the generation of a VRC01-like
antibody from its precursors. The scientists currently are performing research
to identify these components.
The discoveries we have made may overcome the limitations that have long stymied
antibody-based HIV vaccine design," says Dr. Kwong.
Notes:
The two research teams included NIAID scientists from the VRC, the Laboratory of
Immunoregulation, and the Division of Clinical Research, all in Bethesda, Md.;
as well as researchers from Beth Israel Deaconess Medical Center in Boston;
Columbia University in New York; Harvard Medical School and Harvard School of
Public Health in Boston; The Rockefeller University in New York City; and
University of Washington in Seattle.
References:
Wu X et al. Rational design of envelope surface identifies broadly neutralizing
human monoclonal antibodies to HIV-1. Science. 2010.
Zhou T et al. Structural basis for broad and potent neutralization of HIV-1 by
antibody VRC01. Science. 2010.
10 Jul 2010
Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced the publication of data
demonstrating the preclinical efficacy of a human stem cell therapy for human
immunodeficiency virus (HIV) based on its proprietary zinc finger DNA-binding
protein nuclease (ZFN) technology. The ZFN approach enables the permanent
disruption of the CCR5 gene, which encodes an important receptor for HIV
infection, in all the cell types comprising the immune system that develop from
hematopoietic stem cells (HSCs), and is the basis for a promising therapeutic
strategy for the treatment of HIV/AIDS. Sangamo has two ongoing Phase 1 clinical
trials to evaluate the safety and clinical efficacy of this approach in CD4+
T-cells.
The work, which was carried out in the laboratory of Paula Cannon, Ph.D.,
Associate Professor of Molecular Microbiology & Immunology at the Keck
School of Medicine of the University of Southern California (USC), in
collaboration with Sangamo scientists, was published on July 2, 2010, as an
Advance Online Publication in Nature Biotechnology.
"These are very exciting data that provide proof of concept for a new
approach to HIV treatment," said John Zaia, M.D., the Aaron D. and Edith
Miller Chair in Gene Therapy and Chair of Virology, City of
Dr. Zaia is the leader of the recent $14.5 million Disease Team Research Award
granted by the California Institute for Regenerative Medicine (CIRM) to a
multidisciplinary team of investigators which includes City of Hope, Dr. Cannon
and her colleagues at USC, and Sangamo scientists. The award funds the
preclinical development of a ZFN CCR5-targeted approach which aims to complete
an Investigational New Drug (IND) application to the U.S. Food and Drug
Administration (FDA) for clinical testing of this ZFN method.
Sangamo's ZFNs are designed to permanently modify the DNA sequence encoding
CCR5, a co-receptor that enables HIV to enter and infect cells of the immune
system. Individuals carrying a naturally occurring mutation of their CCR5 gene,
a variant known as CCR5-delta32, have been shown to be resistant to HIV
infection. Building on this observation, a study published in the New England
Journal of Medicine in 2009 reported a potential "cure" when an AIDS
patient with leukemia received a bone marrow transplant from a
"matched" donor with this delta-32 CCR5 mutation. This approach
transferred the HSCs residing in the bone marrow from the delta-32 donor, and
provided a self-renewable and potentially lifelong source of HIV-resistant
immune cells. After transplantation, the patient was able to discontinue all
anti-HIV drug treatments, CD4 counts increased, and viral load dropped to an
undetectable level, demonstrating effective transplantation of protection from
HIV infection. The data reported in the Nature Biotechnology publication
replicate these findings for a ZFN-based treatment in a preclinical model.
"The data described in this paper are an important demonstration of the
potential therapeutic possibilities of ZFN modification of human stem
cells," commented Philip Gregory, D. Phil., Sangamo's vice president of
research and chief scientific officer. "We have demonstrated efficient and
specific modification of human hematopoietic stem cells, rendering them
resistant to infection with HIV-1 while retaining their 'stemness' and ability
to differentiate. These data pave the way for the use of this technology in
other diseases for which HSC modification may be therapeutically useful."
Data Reported in the Nature Biotechnology Paper
The reported results demonstrate that a one-time exposure to CCR5-specific ZFNs
resulted in the generation of an HIV-resistant population of human HSCs by the
permanent genetic modification of the CCR5 gene. These ZFN-modified stem cells
engrafted in NSG (NOD/SCID/IL2rγnull) mice, which lack a normal immune
system and are able to tolerate engraftment of human cells and tissues. After
8-12 weeks the engrafted ZFN-modified human cells could be identified as
different immune cell types in the peripheral blood, and various tissues of the
mouse suggesting that they were functionally normal. Furthermore, the ZFN-modified
HSCs produced progeny that could be harvested from one mouse and engrafted into
a second animal, demonstrating that the modified HSCs retain their 'stemness'
and ability to differentiate. In addition, the animals did not experience any
obvious toxicity or ill-health. In HIV challenge experiments, researchers found
that the ZFN-modified cells had a selective advantage over unmodified HSCs and
not only survived infection but expanded and appeared to traffic normally to
various tissues in the mouse. Moreover, the presence of ZFN-modified cells
controlled HIV replication in the animals. These data suggest that human HSCs
can be modified with ZFNs, expand and differentiate and have a selective
advantage in the presence of HIV allowing them to evade infection and
destruction leaving them able fight opportunistic infections and HIV itself.
About HIV/AIDS and CCR5
Human Immunodeficiency Virus (HIV) infection kills or impairs cells of the
immune system, progressively destroying the body's ability to fight infections
and certain cancers resulting in AIDS (Acquired Immune Deficiency Syndrome).
Individuals diagnosed with AIDS are susceptible to life-threatening diseases
called opportunistic infections, which are caused by microbes that usually do
not cause illness in healthy people. According to UNAIDS/WHO, over 2.7 million
people were newly infected with HIV in 2007. An estimated 2.0 million people
died of AIDS in the same year. There are now over 33 million people living with
HIV and AIDS worldwide. The CDC estimates that, in the
CCR5 is the chemokine receptor that HIV uses as a co-receptor to gain entry into
immune cells. CCR5 is perhaps the most important of the known co-receptors for
HIV, since the most commonly transmitted strains of HIV are strains that bind to
CCR5 -- so-called "R5" strains. A small fraction of the population
carries a mutation in their CCR5 gene, called the delta32 mutation. This mutated
version of the gene results in a truncated CCR5 protein which cannot be used by
HIV as a co-receptor. Individuals that have mutant delta 32 versions of both of
their CCR5 genes are resistant to infection by R5 HIV strains.
About Sangamo
Sangamo BioSciences, Inc. is focused on the research and development of novel
DNA-binding proteins for therapeutic gene regulation and modification. The most
advanced ZFP Therapeutic™ development program is currently in a Phase 2b
clinical trial for evaluation of safety and clinical effect in patients with
diabetic neuropathy and a Phase 2 trial in ALS. Sangamo also has two Phase 1
clinical trials to evaluate safety and clinical effect of a treatment for
HIV/AIDS and another Phase 1 trial to evaluate safety and clinical effect of a
treatment for recurrent glioblastoma multiforme. Other therapeutic development
programs are focused on neuropathic pain, nerve regeneration, Parkinson's
disease and monogenic diseases. Sangamo's core competencies enable the
engineering of a class of DNA-binding proteins known as zinc finger DNA-binding
proteins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence
Sangamo has created ZFP transcription factors (ZFP TF) that can control gene
expression and, consequently, cell function. Sangamo is also developing
sequence-specific ZFP Nucleases (ZFN) for gene modification. Sangamo has
established strategic partnerships with companies in non-therapeutic
applications of its technology including Dow AgroSciences and Sigma-Aldrich
Corporation.
July 8, 2010
The controversial heroin
substitute methadone improves the long-term survival of drug abusers, according
to academics.
A study showed the
treatment reduced the frequency of drug use and led to a drop in the risk of
death by 13% each year.
But the findings also
showed the drug can prolong the number of years users continue to inject heroin.
Injecting can kill through
overdose and the transmission of HIV and hepatitis. A recent outbreak of anthrax
in
The research was carried
out by the universities of
Roy Robertson, a GP who
led the study at the
"Our research shows
that despite this they still gain substantial health benefits from their
prescription.
"Suggestions that
methadone prescribing should be cut back or confined to the short-term are
clearly misplaced and would lead to poorer health for drug injectors."
The research comes three
months after a group of 40 experts from around the world said methadone should
be "readily available" to addicts seeking help.
They argued that scrapping
the treatment could lead to a rise in crime and drug deaths. But its use has
been criticised by Scottish Conservatives, who claimed addicts are
"parked" on methadone.
08 Jul 2010
The National Institute for Health and Clinical Excellence (NICE) has today (8
July) published its draft clinical guideline on diagnosing latent TB in children
and adults. A partial update of its 2006 guideline, the draft focuses on the
diagnosis of latent TB using tuberculin skin tests (TST, also known as Mantoux
and Heaf tests) and the newer interferon-gamma tests (IGT). The draft addresses
which diagnostic strategy is most accurate in diagnosing latent TB in adults and
children who are recent arrivals from countries where TB is highly prevalent; in
adults and children who have been in close contact with patients with active TB,
and in adults and children who are immunocompromised.
The original NICE guidance recognised that there was a lack of good quality
evidence to show whether interferon-gamma tests are acceptable to patients and
are more effective than tuberculin skin tests for predicting subsequent
development of active TB, or diagnosing or ruling out current active TB. NICE
therefore recommended further research to compare the strategies of skin test
only, skin test then interferon gamma test if positive, and interferon gamma
test only. Concern was also raised about the appropriateness of IGT use in
current clinical practice during the planned review process for the original
NICE guideline on the diagnosis and management of TB.
Based on a detailed analysis of this further research, the independent Guideline
Development Group (GDG) has concluded that the relative benefit of IGT over TST
in determining the need for treatment of latent TB infection is not certain -
and in the case of younger children it feels that IGT may even perform less
well. However, the GDG has made recommendations in populations where they
considered IGT to be of clear benefit, especially in cases where IGT would
reduce the uncertain diagnosis of TST. Recommendations in the draft guideline
therefore include the following:
To diagnose latent TB in:
-- Household contacts 5 years and older, non household contacts and adult
contacts:
- A Mantoux test should be performed. Those with positive results (or in whom
Mantoux testing may be less reliable) should then be considered for IGT.
-- Recent arrivals from highly prevalent countries aged 5 - 34 years:
- Offer a Mantoux test followed by IGT if positive.
-- Recent arrivals from highly prevalent countries aged 16 years and above:
- An IGT test alone can be used.
-- Recent arrivals from highly prevalent countries aged under 5 years:
- Use Mantoux as the initial test. If positive, taking into account BCG history,
undertake clinical assessment to exclude active disease and consider treatment
of latent TB.
-- People who are immunocompromised:
- For people with HIV and CD4 counts (also called T-cells, these are types of
cells that help protect the body from infection) of less that 200, perform both
an IGT test and a TST. If either test is positive assess for active TB. Consider
treatment of latent TB if active disease is excluded.
- For people with HIV and CD4 counts of 200-500, perform an IGT test alone or
and IGT test with concurrent TST. If either test is positive, assess for active
TB. Consider treatment of latent TB.if active disease is excluded.
Dr Fergus Macbeth, Director of the Centre for Clinical Practice at NICE said:
"If TB is left untreated it can be very serious or fatal but antibiotic
treatments are highly effective. Up to 15% of adults with latent TB will go on
to develop active TB at some point in their lives and the risk in children may
be much higher. In people who are immunocompromised - for example, if they are
HIV positive - the chance of developing active TB within five years of infection
is up to 50%. Detection of latent TB is therefore important in controlling the
disease.
He continued: "The newer interferon gamma tests for latent TB may offer
some advantages over the current internationally recognised standard test - the
Mantoux test. However, despite the studies that have been carried out since the
original NICE TB guidance was published, important questions remain unanswered
about the potential role of these new tests in clinical practice in the
Stakeholders wishing to submit their comments on the draft guideline are invited
to do so via the NICE website by 5 August 2010. NICE plans to publish its final
guideline in December 2010.
Notes
About tuberculosis
1. Tuberculosis (TB) is an infectious disease caused by the bacterium
Mycobacterium tuberculosis, also known as 'the tubercle bacillus'. TB commonly
affects the lungs, but can also affect other parts of the body. The symptoms of
TB are varied and depend on the site of infection. General symptoms may include
fever, loss of appetite, weight loss, night sweats and tiredness.
2. TB is usually spread by coughs, but prolonged close contact with a person
with TB is usually necessary for infection to be passed on. It can take many
years for a person infected with M. Tuberculosis to develop active TB.
3. Latent TB is where the person has been exposed to the tubercle bacillus,
which remains in the body, but where there are no symptoms of TB.
4. In the
5. Although rates of the disease are now very low in some parts of the country,
in other areas, mainly cities, rates of the disease are higher and, in some
cases, increasing. For example, two in every five cases of TB occur in
6. Almost all cases of clinical TB in the
7. In people with latent TB, 10-15% of adults will go on to develop active TB at
some point in their lives and the risk in children may be much higher. However,
in people who are immunocompromised (for example, if they are HIV positive), the
chance of developing active TB within 5 years of infection is up to 50%.
About the draft guideline
1. There is no gold-standard test for latent tuberculosis. Diagnosis has in the
past relied on the TST but this has poor specificity if there has been BCG
vaccination or exposure to environmental (non-tuberculous) mycobacteria, which
can lead to false positive results. The test results have to be interpreted
within a certain timescale, and patients who do not return, or delay returning,
will have either no result or a possibly inaccurate one.
2. recently, selective immunological (interferon-gamma, or IGT) tests have been
developed using two tuberculosis antigens, 'early secretion antigen target 6'
(ESAT-6 ) and 'culture filtrate protein 10' (CFP-10), which are not present in
BCG, and are found in only a few species of environmental mycobacteria. These
tests can be done on either cells or cell products derived from whole blood.
These tests aim to be more specific by removing false positive results, and to
be better correlated with latent infection or dormant organisms.
3. NICE was asked by the Dept of Health to produce a short clinical guideline on
interferon-gamma immunological testing for diagnosing latent TB (partial review
of CG33) and make recommendations on:
- Which diagnostic strategy is most accurate in diagnosing latent tuberculosis
in adults and children who are recent arrivals from highly prevalent countries?
- Which diagnostic strategy is most accurate in diagnosing latent tuberculosis
in children?
- Which diagnostic strategy is most accurate in diagnosing latent tuberculosis
in adults and children (children considered as a separate population) who have
been in close contact with patients with active tuberculosis?
- Which diagnostic strategy is most accurate in diagnosing latent tuberculosis
in immunocompromised patients?
4. The draft clinical guideline is available (from 8 July 2010) on the NICE
website.
Source:
NICE
Wed, Jul 7 2010
By Frederik Joelving
In fact, they report in
the Annals of Internal Medicine, the rate of sexually transmitted diseases
(STDs) in older men taking erectile dysfunction drugs like Viagra is twice as
high as in their non-medicated peers.
In both groups, however,
the numbers are swelling. According to the Centers for Disease Control and
Prevention, there were more than six new cases of STDs per 10,000 men over 40 in
2008, up almost 50 percent since 1996.
"Younger adults have
far more STDs than older adults, but the rates are growing at far higher rates
in older adults," said Dr. Anupam B. Jena of
While the reasons for this
development aren't well understood, he said more divorces and better health
might have conspired to boost sexual prowess and activity among graying heads.
The problem, however, is
that older adults appear to flout safe sex practices. For instance, the
researchers note, 50-year-olds are six times less likely to use a condom than
men in their 20s.
"We are typically
unaccustomed to practice safe sex over the age of 50, because the risk of
pregnancy is eliminated,"
To test whether the
introduction of Viagra in 1998 might explain some of the STD surge,
The most commonly found
STD was HIV, followed by chlamydia, syphilis and gonorrhea.
Among the few percent of
men who had filled prescriptions for erectile dysfunction drugs, more than two
in a thousand had been treated for an STD in the year before they got the drug.
A year later, the number
dropped to half that, suggesting that Viagra and its chemical cousins didn't
fuel STDs.
However, the risk of
contracting an STD turned out to be more than twice as high in men taking
erectile dysfunction drugs compared with those who didn't.
"These users have a
different sexual risk profile than non-users," said
In an editorial, Dr.
Thomas Fekete, of Temple University School of Medicine in
He added that prevention
strategies should still be directed at younger age groups, whose STD risk is at
least 10 times higher than in middle-aged and older adults.
Still, he said, the
authors remind us "that men older than 40 years remain sexually active,
even if they need chemical assistance to do so. This study also serves as a
reminder that sex after age 40 years is not necessarily safe."
His advice? "Look,
just realize that you are at higher risk for STDs, and try to be careful like
you used to be 30 years ago."
SOURCE: www.annals.org/
Annals of Internal
Medicine, online July 5, 2010.