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November 21,
2010)
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2010-11-20
Researchers at
The study has marked the
"beginning of a fascinating story that will shed new light on an important
but still poorly understood aspect of the interaction of HIV with natural killer
cells," according to an editorial in the journal.
Edward Barker, lead author
of the study said, "With this information, we now have a major new target
for drug therapies that could potentially stop HIV and allow the body's natural
killer cells to do what they are designed to do - protect the body from this
lethal virus."
HIV, like any virus,
infects a cell, replicates itself over and over, and spreads throughout the body
by using its "accessory" proteins to both take over the machinery of
the cells it inhabits and thwart the arsenal of immunological cells that might
destroy it.
Oddly, some of these
proteins work at cross-purposes. One, the Vpr protein, initiates what is called
DNA damage repair, stopping the host cell in its tracks so that the virus can
take over.
But that action also sends
a message to the cell surface that something is amiss. A ligand, called ULBP, is
sent to the surface of the cell, which the prowling natural killer cells
recognize and latch onto - the initial steps just before moving in for a kill.
Meanwhile, another protein
produced by HIV prevents the cytotoxic T cells of the immune system from homing
in on the HIV-infected cell and obliterating it. But this same protein also
provokes the natural killer cells into action by shutting down an inhibitory
mechanism that would hold the killer cells back.
If all worked as it should
to protect the body from HIV, the natural killer cells would start firing their
lethal pellets. But they don't, and that is what has puzzled scientists for so
long.
"The barrel of the
shotgun is loaded, but the trigger still has to be pulled," said Barker.
Barker and his colleagues
now know why the trigger is not pulled: ecause yet another protein, called NTB-A
(for Natural killer T-cell and B-cell Antigen), has virtually disappeared from
the surface of the infected cell. Without NTB-A in place, the natural killer
cells don't start firing the guns.
The culprit, the
researchers found, is a protein made by HIV called Vpu, which holds NTB-A inside
the cell and prevents it from reaching the cell surface.
When the researchers
altered the Vpu protein, allowing NTB-A to migrate to the cell membrane, the
natural killer cells blasted the HIV-infected cells - proof that both the ULBP
ligand and NTB-A are needed before the natural killer cells will start shooting.
The findings were reported online in the journal Cell Host and icrobe. (ANI)
2010-11-21
The scientists based their
conclusion on the results of a series of crystallography and biochemical
experiments that revealed the specific molecular structures different types of
antibodies need to have in place in order for them to mount an effective
defence.
Previous research had
shown that two of the most robust antibodies against HIV -antibodies called 2F5
and 4E10 - target a specific part of the outer coating of the virus called the
MPER region of gp41.
The antibodies, which
operate in a lock and key relationship, are able to latch on to the virus as it
reveals this vulnerable part of its structure, referred to as an 'Achilles heel'
of the AIDS virus.
"What our studies
revealed, however, is that the virus actually creates two versions of this
'Achilles heel,' said Barton Haynes of the Duke Human Vaccine Institute (DHVI).
"One version is for
these rarer, broadly-neutralizing antibodies, and the other is for the more
abundant, first-responding antibodies that won't be able to do much good because
the Achilles heel isn't detectable to them until the virus has already gained
entry," said Haynes.
Nathan Nicely, the lead
author of the study and a member of the DHVI, designed and conducted most of the
crystallography studies.
"This structure has
been difficult to obtain, but now that we have it, it has been instrumental in
our understanding why this non-neutralizing antibody interacts with the HIV-1
outer coat," said Nicely.
Haynes said the findings
are important because they distinguish what parts of the virus an antibody needs
to recognize from those parts that are decoys.
"We are homing in on
a better understanding of what the immune system needs to do in order to mount
an effective defense against HIV," he added.
The study has been published in the Journal Nature. (ANI)
Nov 16, 2010
Scientists have solved one
of the great mysteries of the HIV/AIDS virus: why it is so successful at
breaking down the body's resistance.
A paper in the journal
Nature, published today, lays out the reasons why humans do not produce
antibodies against the virus.
This lack of a natural
defence allows the virus to enter cells without being attacked.
The findings offer new
hope for vaccines which could target HIV/AIDS more effectively.
The key is a potential
weak link, a protein on the surface of HIV called gp41, which helps the virus
invade cells.
Professor Stephen Kent, an
immunologist at the
"The GP41 component
is the component that essentially punches a hole in the membrane or the surface
of the cell and allows the virus to get in," he said.
"It's a very critical
component of the entry mechanism of the virus.
"If we can prevent
the HIV from getting into cells, then we'd have a great vaccine."
It has been known for many
years that about one in 1,000 people can naturally control the HIV virus, by
making an antibody against gp41.
The work published in
Nature shows that while most people do develop an antibody against gp41, they do
this after the virus has already entered their cells.
"They're making a
response against this gp41 after the horse has already bolted," Professor
Kent said.
"And so the virus
gets in, it infects, it destroys these CD4 cells, and only then is the antibody
made.
"It's disappointing,
but at the same time it's also a clue. As we understand this better we can now
try and direct our efforts against the specific parts of gp41 that we can attack
before the virus can get into the cell.
"It's perhaps a
couple of steps back and one step forward for HIV vaccine research."
Nov 18 2010
By Gene Emery
The finding, published in
Thursday's New England Journal of Medicine, is good news for people with the
virus, who are more prone to kidney disease, in part because of the drugs they
must take to stay healthy.
Before drug cocktails
turned HIV from a death sentence to a chronic condition, patients were not
eligible to receive a kidney.
But now they can.
"Patient and graft survival are really pretty good and it approximates the
general population," Dr. Peter Stock of the
But the news was not
uniformly good. Rejection rates were two to three times higher than normal,
which surprised Stock.
"It's not that
dramatic and we've been able to reverse them," said Stock. "But we
know that each rejection episode takes a little bit of life out of a kidney. So
instead of lasting 20 years, it might last 15 years. That's why it's very
important to figure that out."
His team studied 150
patients treated at 19
The patients, who were
followed for up to three years after their transplants, had a 95 percent
survival rate at one year and an 88 percent rate by the three-year mark. Ninety
percent of the kidneys were still functioning after one year; 74 percent by the
third year.
Those success rates are
between what would be expected for all recipients and those age 65 and older.
Eleven of the 150 died.
The deaths were caused by heart problems, cancer in the old kidney, bacterial
and lung infections.
Stock said there was no
evidence that the transplant process caused a resurgence of the HIV, even though
the number of protective white blood cells did initially decline.
"HIV simply doesn't
progress," said Stock, adding that the same phenomenon has been seen among
liver transplant recipients.
In the past, doctors had
been concerned that the drugs needed to prevent rejection of the kidney might
interfere with the drugs that keep the virus under control.
In a commentary, Dr. Lynda
Anne Szczech of
SOURCE:
By Jean-Louis Santini (AFP)
– 5 days ago
In both cases, one in the
western state of
The findings published in
the Proceedings of the National Academy of Sciences describe how scientists were
able to narrow down the exact type of HIV that matched both the accused
criminals and the women they infected.
The research marks a
breakthrough in scientists' ability to say definitively which person was the
source of the infection.
"This is the first
case study to establish the direction of transmission," said Michael
Metzker, associate professor in the Baylor College of Medicine Human Genome
Sequencing Center in
Scientists were
"blinded" in the studies, meaning they were unaware which samples came
from the accused and which came from the women.
The process was
complicated because of the way HIV presents itself in an infected person, said
Metzker.
"Within a given
person, there is not just one strain but a population of strains because HIV
mutates all the time when it makes new virions (viral particles)," said
Metzker.
"During transmission,
however, there is a genetic bottleneck in which only one or two viruses get
transmitted to the recipient."
By narrowing down the
single "ancestor" of HIV and comparing two distinct gene regions of
the virus across different subjects, scientists were able to reconstruct the
history of the virus -- in a process known as phylogenetic analysis.
But more importantly, the
scientists were able to decipher which sample was the source of the infection.
"We can identify the
source in a cluster of infections because some isolates of HIV from the source
will be related to HIV isolates in each of the recipients," said study
coauthor David Hillis of the
After the analysis was
done, scientists handed over their results, showing which sample they believed
was the source of the HIV infection and which samples were the recipients.
Prosecutors then linked
the samples to the suspects, in each case making a perfect match to the person
they suspected of being responsible for the women's HIV infections.
As a result, Philippe
Padieu was sentenced by a
And in
A prior study was able to
link patients with the same viral sequences in the southern state of
In that situation, a
doctor was accused in 1998 of having taken blood samples from patients infected
with HIV and hepatitis C and injecting them into his ex-girlfriend, who later
developed HIV.
However scientists knew to
whom the samples belonged, so their study was not entirely objective, said
Metzker.
Copyright © 2010 AFP
Nov. 17, 2010
Significant T-cell
responses demonstrate potential of PENNVAX(TM)-B HIV DNA vaccine delivered using
electroporation
Inovio previously reported
data from non-human primates demonstrating up to a 100-fold enhancement in
immune responses resulting from the vaccine when delivered via in vivo
electroporation compared to syringe injection without electroporation. This
study, designated HVTN-080, involved vaccination of 48 healthy, HIV-negative
volunteers to assess safety and levels of immune responses generated by Inovio's
PENNVAX-B vaccine delivered with its CELLECTRA(R) electroporation device.
PENNVAX-B is a SynCon(TM) DNA vaccine that targets HIV gag, pol, and env
proteins. This randomized, double-blind, multi-center study is being sponsored
by the National Institute of Allergy and Infectious Diseases (NIAID), an agency
of the National Institutes of Health, and conducted by the NIAID-funded HVTN, at
several clinical sites.
Of the 48 total
volunteers, eight subjects received a placebo, 10 subjects received a 1 mg dose
of PENNVAX(TM)-B vaccine, and 30 subjects received a 1 mg dose of PENNVAX-B
along with IL-12 DNA. The IL-12 for this study (Genevax-IL-12), manufactured
under a contract with DAIDS, was provided by Profectus Biosciences. All
volunteers received vaccine or placebo administered with electroporation at
months 0, 1, and 3. The T-cell immune responses were detected using a validated
flow cytometry-based intracellular cytokine staining (ICS) assay at the HVTN
core immunology laboratory at the
Preliminary data from the
trial reported at the meeting included safety data from all trial participants
(48) and immunogenicity data from 38 out of 40 samples from vaccine recipients
post-second-dose and from 31 out of 40 samples from vaccine recipients
post-third-dose. The data indicate that antigen-specific T-cell responses were
generated by the vaccine in a majority of subjects. Either CD4+ or CD8+ or both
T-cell responses were observed against at least one of the vaccine antigens in
61% (23 out of 38) of evaluated subjects after two vaccinations. After three
vaccinations, 84% (26 out of 31) of evaluated subjects had positive T-cell
responses.
Notably, after three
vaccinations:
67% (6 out of 9) of
evaluated subjects receiving PENNVAX-B and 91% (20 of 22) of evaluated subjects
receiving PENNVAX-B + IL-12 were observed to have generated antigen-specific
T-cell responses (either CD4+ or CD8+). Antigen-specific CD4+ T-cell responses
were generated by the vaccine in 70% of evaluated vaccine recipients (21 out of
30). Significantly strong antigen-specific, CD8+ T-cell responses were also
generated by the vaccine in 55% of evaluated vaccine recipients (17 out of 31).
Samples from eight placebo recipients and pre-vaccine samples from vaccine
recipients were also tested and were negative for both CD4+ T-cell responses and
CD8+ T-cell responses. PENNVAX-B delivered using the CELLECTRA(R) intramuscular
electroporation delivery device with or without IL-12 was generally safe and
well tolerated. There were no vaccine-related serious adverse events. Reported
adverse events and injection site reactions were mild to moderate and required
no treatment.
Dr. Kalams stated,
"The preliminary immune response data from this novel DNA-based vaccine are
indeed very encouraging. We look forward to our continuing work with Inovio to
develop the potential of this promising vaccine candidate."
Dr. J. Joseph Kim,
Inovio's President and CEO, said: "After recently announcing best-in-class
immunogenicity data from our clinical trial for our cervical cancer DNA vaccine
using the same technology platform, we are pleased to again see very strong
T-cell immune responses from this vaccine platform for a different disease, and
particularly a disease with unmet needs like HIV. They are amongst the highest
immune responses seen in other HIV vaccine trials either with DNA or other
vaccine platforms including proteins and viral vectors. However, unlike viral
vectors, DNA vaccines do not induce unwanted immune responses against the
carrier. Taken together these results further support the prospect that Inovio's
DNA vaccine and delivery platform could play an important role in developing new
vaccines and therapies for major diseases like cancer and HIV."
In addition to the interim
ICS results presented at the meeting, the complete immunogenicity data including
data from the few remaining unanalyzed samples and additional antibody and
T-cell results based on ELISpot assays as well as the end-of-study safety data
are expected in 2Q 2011.