[Viva] Fwd: CATIE News - Hints of a cure: the future of stem cell transplants and HIV

[Denise Becker]

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From: <mailing at mercury.catie.ca>
Date: Wed, Dec 22, 2010 at 9:51 AM
Subject: CATIE News - Hints of a cure: the future of stem cell transplants
and HIV
To: dbecker106 at gmail.com


CATIE News - Hints of a cure—the future of stem cell transplants and HIV

In 2008 a team of cancer researchers from Berlin, Germany, reported an
important result—an HIV-positive patient with leukemia was treated with a
unique stem cell transplant and not only did he recover from leukemia but
researchers could no longer detect HIV in his blood samples.

In December 2010, further analyses from this man, dubbed the “Berlin
patient,” became available. In these analyses the German team is still
unable to detect HIV in his blood and now also his tissues, and the
researchers suggest that he may be cured.

Although these results are extremely promising for the Berlin patient,
because of several issues (explained later in this report) stem cell
transplant technology available today will not result in curing HIV
infection for most people. The good news is that the German results uncover
an exciting avenue for research that might one day lead to better therapies,
stronger immune systems and possibly a cure for HIV-positive people.
Attempts to repeat the success of the Berlin patient are planned or underway
in Western Europe and Israel.
*Case details*

In February 2007, a 40-year-old man, HIV positive for 10 years, sought care
at Berlin’s Charité University medical centre because of a diagnosis of
leukemia. For four years prior to his leukemia diagnosis he had been taking
the following medicines for HIV infection:

   - efavirenz (Sustiva and in Atripla) 600 mg/day
   - FTC (emtricitabine, Emtriva) 200 mg/day
   - tenofovir (Viread and in Truvada and Atripla) 300 mg/day

His CD4+ count was 415 cells and his viral load was less than 50 copies/ml.
*Leukemia treatment*

The man received chemotherapy and developed severe liver and kidney
toxicity. As a result, his doctors discontinued highly active antiretroviral
therapy (HAART) but then his viral load became very high—nearly 7 million
copies/ml. Stunned by this immense increase in viral load, his doctors
reinstated HAART and within three months his viral load fell to less than 50
copies/ml and the leukemia went into remission.
*A rare mutation*

Seven months after the man’s initial leukemia diagnosis, the cancer
returned. This time, his doctors proposed a bone marrow transplant. The
donor of the bone marrow not only had a similar genetic makeup to the man,
but he also had a rare genetic mutation that affected his immune system. The
mutation, referred to by scientists as delta-32, resulted in the donor’s
cells missing one of the proteins or receptors that HIV needs to enter and
infect a cell. This receptor is called CCR5. The delta-32 mutation carried
by the blood donor is extremely rare, found in about 1% of people of
northern European ancestry. This rare delta-32 mutation is perhaps the most
important aspect of the German report, and in the next section we explain
why.
*Know your receptors*

HIV needs at least two receptors to enter and infect a cell. The first
receptor is CD4+, which is found on many immune system cells. HIV usually
then needs one of two other co-receptors, either CCR5 or CXCR4.

Some strains of HIV prefer to use CCR5, others CXCR4, and still others use
both co-receptors. The bone marrow donor had the delta-32 mutation, and so
his immune system lacked CCR5 receptors. Because the lack of CCR5 receptors
makes cells somewhat resistant to HIV infection, the Berlin patient’s
doctors hoped that a transfusion of stem cells from the donor would
eventually transform and give rise to a fresh immune system for him that was
at least partially resistant to HIV.
*Preparing for the stem cells*

The Berlin patient’s body was subjected to intensive chemotherapy for
several days, and then he was blasted with radiation. In addition, doctors
infused antibodies that attacked his immune system. As if that was not
enough, they gave him several transplant drugs—including cyclosporine—all in
an attempt to further weaken his immune system. The reason for such an
intensive attack on his immune system was to allow the stem cells that he
would subsequently receive to survive assaults by the remnants of his immune
system. As his old immune system died, the doctors hoped that the
transplanted stem cells would behave as if they were his and occupy the bone
marrow and begin to divide, transform and mature into the many types of
cells needed by the immune system.

Thirteen days after infusing him with stem cells, doctors confirmed that the
transplanted cells had adapted to their new host and were beginning to
rejuvenate his immune system.
*The battle within*

Sometimes a complication of transplantation called graft versus host disease
(GvHD) occurs when cells from the donor attack the host’s body. Organs
commonly attacked in GvHD include the skin, liver and intestines.

In the case of the Berlin patient, doctors stated that he only had mild skin
damage from GvHD, presumably because they administered several
immune-suppressing drugs as follows:

   - cyclosporine (Sandimmune, Neoral)
   - Cellcept (mycophenolate mofetil)
   - prednisone

The effects of chemotherapy, radiation and additional immunosuppressive
drugs can weaken both the remnants of the old immune system and the emerging
new immune system. Life-threatening infections and other complications can
consequently occur. Fortunately, the Berlin patient was spared these.
*Relapse and recovery*

Thirteen months after transplantation, the Berlin patient’s leukemia
recurred and he again received chemotherapy and radiation followed by
another infusion of stem cells from the same donor. He recovered from
leukemia and remains in remission three and a half years after his
transplant.
*Brain problems*

About a year and half after his first transplant, the Berlin patient
experienced several neurologic problems suggestive of a brain infection
called leukoencephalopathy. This can be caused by JC virus, which is
commonly found in humans. JC virus can cause complications in people whose
immune systems are severely weakened, such as those with AIDS or who are
taking transplant medicines. Infection with JC virus damages the insulating
sheath that covers nerve cells. Because the layer of insulation has
degraded, signals sent by nerves can leak and become weakened. As a result,
muscle control becomes difficult, speech and vision become impaired and even
personality changes can occur.

MRI scans of the man’s brain suggested inflammation perhaps caused by JC
virus infection, so surgeons removed a small amount of brain tissue for
analysis. However, they could not detect any JC virus and proposed that his
symptoms were caused by the toxicity of so much chemotherapy and radiation.
Such problems can occur even months after chemotherapy or radiation have
ceased.

The man’s neurologic symptoms spontaneously cleared and three years after
his initial transplant, his doctors discontinued giving him
immune-suppressing drugs. No GvHD has recurred.
*What happened to HIV and his immune system?*

Only about 2% of the body’s lymphocytes are found in the blood. Most of
these cells are in the lymph nodes and lymph tissues scattered around the
intestines. So, most HIV in the body is also found in these lymph nodes and
tissues.

But lymphocytes are not the only cells attacked by HIV. Macrophages, another
important group of cells, also have CD4+ and other receptors used by HIV to
infect them. Macrophages are particularly important because, unlike T-cells,
they can live longer even though they may become infected with HIV.
Moreover, infected macrophages can rove throughout the body, entering and
leaving organs and spreading HIV in the process. Some macrophages even
become specialized and take up residence within certain organs, such as the
brain, liver, bone marrow and so on, where they guard against infections.

Researchers took samples of tissue from the man’s brain, bone marrow, liver
and intestines to find cells of the immune system and assess them for the
presence of HIV. However, they could not detect any infected cells or HIV in
the man’s tissues or blood. The Berlin researchers are not certain why HIV
did not rebound after the stem cell transplant.

The stem cell transplant has not rendered the man entirely immune from HIV
infection should he be exposed in the future. He will therefore need to
practice safer sex.

In lab experiments done after transplantation, cells from the man’s new
immune system remain susceptible to HIV. Specifically, the researchers added
HIV to cultures of CD4+ cells from the man. Only HIV that uses the
co-receptor CXCR4 to gain entry to cells is able to cause infection because
the man’s new immune system does not have CCR5 co-receptors.

Biopsies of lymph tissues from his intestines suggest that the stem cell
transplant has helped to form a new immune system. His CD4+ cell count in
the blood is now about 800 cells—within the normal range. Although doctors
in Berlin are unable to find HIV in the man, he continues to have antibodies
against this virus in his blood.
*A summary of his course*

An HIV-positive man on HAART survived several bouts of chemotherapy,
radiation and leukemia. Major risks of chemotherapy, radiation and other
immunosuppressive therapy include life-threatening infections and bleeding.
In the short-term, nausea, vomiting, fatigue and hair loss can also occur.
Long-term complications from immunosuppressive therapy include damage to the
liver, lungs, kidneys and heart as well as the formation of new cancers.
Despite all of this, the man’s leukemia is currently in remission.

He received a stem cell transplant from an HIV-negative donor who had a rare
mutation—the absence of a co-receptor called CCR5, used by HIV to infect
cells. This mutation is also called delta-32 by researchers and makes it
difficult for some strains of HIV to infect cells. The delta-32 mutation is
generally rare, and even among people of northern European ancestry who are
most likely to have this mutation, only about 1% do.

The man’s immune system has returned to normal throughout his body and his
CD4+ cell count is within the normal range. Doctors are unable to isolate
HIV from several tissues and organs and suggest that he may be cured of HIV.
*Short-term implications of the Berlin study*

The findings from the Berlin patient are extraordinary and deserve pause for
thought. For the first time it seems that HIV can be cured.

It is still possible that deep within the man’s body there is a very small
amount of HIV that can be controlled by his immune system. This possibility
exists because the gold standard labour-intensive and time-consuming
laboratory procedures that were done by other researchers when investigating
past suggestions of a cure (with different therapies) have not been
conducted.

Unfortunately, because the delta-32 mutation that confers resistance to HIV
is so rare, finding a genetically matched stem cell donor for most other
HIV-positive people is highly unlikely. Indeed, so far, preliminary searches
within European stem cell registries for more potential donors that can be
genetically matched to HIV-positive patients with cancer have yielded only a
handful of potential donors. So, using stem cell transplantation as a
potential cure for HIV cannot be generally implemented even in high-income
countries.

The good news is that the developments in Berlin have stimulated the
imagination of scientists both inside and outside of the field of AIDS
research. Some researchers are designing genetic therapies to make stem
cells resistant to HIV infection by a number of means. Preliminary results
suggest that such therapies are safe, at least in a very small number of
volunteers who have received them. The issue of safety is important for
genetic therapies because in past experiments gene therapies can sometimes
stimulate the formation of tumours. The Berlin doctors are also encouraging
the use of the anti-HIV drug maraviroc (Celsentri, Selzentry) in future stem
cell transplantation experiments with HIV-positive people. Maraviroc covers
the CCR5 receptor on cells and has anti-inflammatory activity; both of these
properties may be useful in future experiments with stem cell transplants in
HIV infection.
*Repeating the experiment*

It is essential that the researchers at Charité University and elsewhere
attempt to repeat the results obtained with the Berlin patient. To this end,
the Berlin team has obtained agreement from leading European stem cell
registries to support further experiments. Stem cell transplants with the
delta-32 mutation in HIV-positive people with cancer are now planned or
underway in at least nine people in Western Europe and Israel. In part, the
reason for this low number is that the delta-32 mutation is so rare.
*Future issues*

Some researchers are designing genetic therapies to make stem cells
resistant to HIV infection by a number of means. Preliminary results suggest
that such therapies are safe, at least in a very small number of volunteers
who have received them with several years of monitoring. The issue of safety
is important for both stem cell transplants and genetic therapies because in
past experiments gene therapy can sometimes inadvertently trigger the
formation of tumours. Here are some issues to bear in mind with such
therapies:

   1. In the medium-term, experiments with stem cell transplants and gene
   therapy attempting to renew the immune system will likely be tested in
   HIV-positive people with leukemia or lymphoma, as such people have the
   greatest need for stem cell transplants.
   2. Long-term monitoring of HIV-positive people who receive stem cell
   transplants together with genetic therapy to render the CCR5 co-receptor
   absent are needed. This need arises not only to be sure that there is no
   increased risk for cancer but also because no one knows the potential
   long-term toxicity of grafting a CCR5-deficient immune system in someone who
   has previously had CCR5 receptors in his/her immune system.
   3. Will intensive chemo- and radiation therapy always be needed for
   HIV-resistant stem cell transplants to be effective in their new hosts? Such
   therapy carries a risk of severe and life-threatening complications. Already
   one young HIV-positive person had died in Israel after an attempted stem
   cell transplant. Stem cell transplants are not usually done in people over
   the age of 60. Can this barrier be overcome?

In the next decade, as scientists gain more experience with making stem
cells resistant to HIV infection, expect to hear more reports about the use
of stem cell therapies to rebuild the immune systems of HIV-positive people.
Hopefully, such reports will also include news about curing HIV infection.

*—Sean R. Hosein*






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