Monday, March 31, 2014

Bone marrow transplant and engineered immune cells HIV hope

~~~~HIV returns in two patients after bone marrow transplant
HIV has returned in two patients who doctors hoped had been cured of the virus
following bone marrow transplants, the Boston researcher who treated them said Saturday.

The HIV virus became undetectable in both patients approximately eight months after
the transplant. The men remained on antiretroviral therapy until the spring of 2013.

"The return of detectable levels of HIV in our patients is disappointing, but scientifically
significant," Dr. Timothy Henrich, a researcher at Brigham and Women's Hospital in Boston,
said in a statement. "We have demonstrated HIV can be reduced to undetectable levels by
very sensitive research assays and the virus persists."

The virus became detectable in one patient in August 12 weeks after ceasing
antiretroviral therapy. In the other man, HIV became detectable this month,
32 weeks after antiretroviral therapy ceased.

"Through this research we have discovered the HIV reservoir is deeper and more
persistent than previously known and that our current standards of probing for HIV
may not be sufficient to inform us if long-term HIV remission is possible if
antiretroviral therapy is stopped," Henrich said. "We have also learned that there may
be an important long-lived HIV reservoir outside the blood compartment."

Dr. Daniel K. Kuritzkes, another researcher at Brigham and Women's Hospital, said
the cases demonstrate that the virus may persist even when there is
no evidence in the blood.

"We need to develop better and more sensitive tools to detect the virus as we continue
to pursue novel strategies for HIV eradication," he said. "Our results also show that
the immune system can play a major role in reducing the viral reservoir, but may not be
able to do the job alone. It is likely that a combination of drugs and immune
therapies that target the reservoir will be needed to establish long-term remission
of HIV infection."

In July, when the cases were first reported at the International AIDS Society Conference
in Kuala Lumpur, Malaysia, experts stopped short of calling the two cured and said the
treatment is not a viable option for the majority of HIV patients.

After the patients ceased antiretroviral therapy, they were tested for HIV every seven to
10 days. Both resumed antiretroviral therapy after the virus was detected.
They are in good health and the virus is suppressing as expected.

Brigham and Women's Hospital researchers will continue to monitor the patients
and measure their HIV levels as part of a new study of the very early initiation of
antiretroviral therapy after HIV rebound.

The men, whose identities were withheld, had been on antiretroviral drug therapy
for years before being diagnosed with lymphoma, a cancer of the lymph nodes.

Both underwent intensive chemotherapy followed by bone marrow transplants to
treat the cancer. They remained on antiretroviral therapy.

Approximately four months after the transplant doctors were still able to detect
HIV in their blood, but six to nine months later, all traces of the virus were gone.

Some patients make it up to eight weeks before the virus returns, but the virus returns
eight to 10 weeks after therapy is stopped in the vast majority of patients,
Henrich said in July. Not so for these two men, however.

HIV discovery 'will change your life forever'

The two men were compared with Timothy Ray Brown, also known as the
"Berlin Patient." Brown is thought to be the first person ever "cured" of HIV/AIDS.

In 2007, Brown had a stem cell transplant to treat his leukemia. His doctor searched
for a donor with a rare genetic mutation called CCR5 delta32 that makes stem cells
naturally resistant to HIV infection.

Today, the virus is still undetectable in Brown's blood, and he is still considered to be
"functionally cured." A functional cure means the virus is controlled and will not be
transmitted to others.

The stem cell transplant procedure, however, is very dangerous because a patient's
immune system has to be wiped out in order to accept the transplant.

Using a stem cell transplant to treat HIV is not for most patients, and only 1% of
Caucasians mostly Northern Europeans and no African-Americans or Asians
have the CCR5 delta32 mutation, researchers say.

The transplant is still not a practical strategy for the majority of HIV patients,
and the risk of mortality is up to 20%, Henrich says.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases
at the National Institutes of Health, agreed.

"This is not a practical approach for someone who does not need a stem cell transplant since
the transplant and its preparation and its subsequent need for chronic immunosuppression
is a risky procedure," Fauci said.

"If you have an underlying neoplasm (tumor) like these patients had, then the risk
outweighs the benefit," he said. "However, if you are doing well on ARVs and you merely
want to get off antiretroviral therapy, then the risk seems greater than the benefit."

HIV 'cure' in toddler offers 'global hope'

Even though the two patients showed a reduction of the virus in the blood, it could
still be in some tissue the brain or gastrointestinal tract, for instance, Henrich said.

Earlier this year, researchers said an HIV-positive baby in Mississippi was given high
doses of three antiretroviral drugs within 30 hours of her birth, with doctors hoping that
would control the virus.

Two years later, there is no sign of HIV in the child's blood, making her the first child
to be "functionally cured" of HIV.

The Foundation for AIDS Research, or amfAR, helped fund the study.

"These findings clearly provide important new information that might well alter the current
thinking about HIV and gene therapy," said amfAR CEO Kevin Robert Frost.

"While stem cell transplantation is not a viable option for people with HIV on a broad
scale because of its costs and complexity, these new cases could lead us to new approaches
to treating, and ultimately even eradicating, HIV."

"Dr. Henrich is charting new territory in HIV eradication research," said
Dr. Rowena Johnston, amfAR vice president and director of research.

"Whatever the outcome, we will have learned more about what it will take to
cure HIV. We believe amfAR's continued investments in HIV cure-based research
are beginning to show real results and will ultimately lead us to a cure in our lifetime."

~~~~New advance: Engineered immune cells seem to block HIV
Scientists claim they have safely introduced engineered immune cells in 12 people
with HIV that have the ability to resist the virus.

Researchers are lauding it as a step toward paving the way to curing the disease.
Typically, patients must stay on HIV treatments the rest of their lives.

"This reinforces our belief that modified T cells are the key that could eliminate the need
for lifelong (antiretroviral drug therapy) and potentially lead to functionally curative
approaches for HIV/AIDS," Dr. Carl H. June, Richard W. Vague Professor in
immunotherapy in the department of pathology and laboratory medicine at
Penn's Perelman School of Medicine in Philadelphia, said in a statement.

Researchers used so-called "zinc finger nuclease (ZFN) technology" what they referred
to as "molecular scissors" -- to modify T cells in the immune system to mimic the
CCR5-delta-32 mutation, a process called gene editing.

The CCR5-delta-32 mutation has been known to make people resistant to HIV,
but is only found in about 1 percent of Caucasians. Timothy Ray Brown, known as the
"Berlin Patient," had both HIV and leukemia, and was believed to be "cured" of AIDS
after he had blood stem cells containing the rare mutation transplanted in 2007.
He said in 2012 that he hadn't taken HIV medication since.

To create the mutation's effect, the researchers infused 10 billion SB-728-T cells into two
groups of patients between May 2009 and July 2012. Between 11 and 28 percent of
the T cells were modified with the ZFN technology. The gene editing limited the amount
of CCR5 proteins that existed on the cells' surface. Without those proteins on
the surface, HIV could not enter the T cells.

Within a week, all the patients saw a surge in their number of T cells due to the infusion.
T cell numbers began to decline over the next few weeks, one of the hallmarks of
HIV infection. Researchers observed that natural, unmodified levels of T cells declined,
but the modified T cell numbers did not go down as much, suggesting they may have
created HIV protection.

Six patients were taken off their antiretroviral drugs for up to 12 weeks starting
four weeks after the infusions, while the other six stayed on the treatment.

The amount of HIV dropped in four of the patients who stopped treatment,
one of whom had viral levels fall below the normal detection limits.
That patient was later discovered to be a part-carrier of the CCR5 genetic mutation.
The researchers said the subject could teach them more about the mutation
in future studies.

The virus did return eventually in all the patients, but the researchers saw that
the decline of the number of modified T cells was significantly less than the
unmodified cells. The study's primary objective was to look at the
infusions' safety.

~~~~The Evolving Genetics of HIV
People can be infected with many different bacteria and viruses but some people get
more sick from these bugs than others. Do our genes cause some of that difference?

The answer is yes--different versions of important genes change how easy it is for a
person to be infected. The study of these genes might lead to new drugs to block or
slow down an infection.

Since the 1980s many people have been afflicted with AIDS, caused by the virus
HIV (human immunodeficiency virus). However, not everyone who is exposed to
the virus gets sick. Scientists have carefully studied people who seem resistant to
HIV infection. What's going on?

The answer comes from an understanding of how HIV interacts with our cells. HIV,
like all viruses, can't make new copies of itself without help. It needs to enter cells
and use their machinery to reproduce and spread throughout the body.

HIV can only enter certain cells. How does it find the right cells? By special proteins
called receptors.

Receptors sit on the outside of cells to receive messages and transmit them into
the cell. HIV grabs onto cells that have a receptor called CD4.

Cells with the CD4 receptor are an important part of the body's system for fighting
all diseases (our immune system). HIV gradually destroys these cells and cripples
the immune system.

It turns out that CD4 isn't enough. Another protein called CCR5 is needed as well.
CCR5, called a co-receptor because it works with CD4, is the door that
opens to allow HIV to enter the cell.

Many people who are resistant to HIV have a mutation in the CCR5 gene called
CCR5-delta32. The CCR5-delta32 mutation results in a smaller protein that isn't on the
outside of the cell anymore. Most forms of HIV cannot infect cells if there is no
CCR5 on the surface.

People with two copies of the CCR5 delta32 gene (inherited from both parents) are
virtually immune to HIV infection. This occurs in about 1% of Caucasian people.

One copy of CCR5-delta32 seems to give some protection against infection,
and makes the disease less severe if infection occurs. This is more common, it is
found in up to 20% of Caucasians.

Should everyone be tested for this mutation? Not necessarily.
It would be dangerous to assume you are completely safe from infection if you have the
CCR5-delta32 mutation.

It's not an airtight guarantee of never getting AIDS. Some unusual types of HIV
can use other proteins for entering cells. Rarely, there have been people who have
two mutant CCR5 genes who have died from AIDS.

Also, CCR5 is not the whole story of immunity to HIV infection. Some resistant people
have been found who have two perfectly normal copies of CCR5. So other genes
also contribute to slowing down HIV infection, and scientists are busy trying to
identify them.

The usefulness of this work is mainly in how it helps us understand how the virus works
and points to new possibilities for drugs to treat infection.

There is hope out there with much real research, it's a matter of time for a cure.
The research is needed but also the concern about "Genetic mutation" for the cure.
To me I see it as going into a fractal zoom of possible side effects.
But it's a road we would have to go down, with the understanding
to ask if it is ineffectual then one should not press on hoping for the
best down the road.

Does the risk outweighs the benefit?

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