A functional cure?

Published: 01 December 2008

Examining the excitement over a bone marrow transplant that eradicated HIV, by Edwin J
Bernard
Jump to

A tantalising possibility?

A promising approach

A functional cure

Limiting factors

Last month, the worlds press reported that a 42-year-old American man living in Berlin had
been cured of his HIV infection following a bone marrow transplant two years earlier.
We last examined the elusive cure for HIV almost three years ago, following media reports of
so-called miracle man Andrew Stimpson and his premature claims that he was cured of HIV
in November 2005.1
Is this latest case just another example of media hype?

A tantalising possibility?

Between 1982 and 1996, reports of over 30 bone marrow transplants in HIV-positive individuals
with advanced disease were published. In some cases, individuals required chemotherapy and
radiation and subsequent bone marrow transplants for non-Hodgkins lymphoma. In other cases,
researchers actively enrolled individuals with AIDS at a time when there appeared to be no other
options and replaced their bone marrow with those from healthy transplanted donors - in some
cases these were not humans, but baboons - in order to attempt to repopulate the individuals
immune system with healthy, HIV-free blood cells.
Although most died due to HIV - or transplant-related complications soon after the procedures two individuals were found to have undetectable HIV RNA and DNA levels in the weeks and
months following the procedures. A review of these reports, written in 1997 and published in
1999, suggested that bone marrow transplantation offered the tantalising possibility of a cure
for HIV.2
Then, last year, French researchers reported on the case of an HIV-positive individual who had
required a bone marrow transplant to treat acute myeloid leukaemia. As well as experiencing
severe graft-versus-host disease (which is when the immune cells from the donated marrow
attack the body of the transplant patient), the man was found to still have detectable viral load
following a post-transplant treatment interruption, and he died 191 days post-transplant. Doctors
concluded that eradication of HIV from the body was unlikely utilising this method.3

A promising approach
Unlike the previously reported cases, the most recent case differs in two important ways:

unusually, despite the high-risk nature of the procedure, the patient is still alive two years
following the transplant.

a transplant donor was sought who specifically had two copies of the natural genetic
mutation (also known as a polymorphism) delta32 CCR5.

People who have acquired two copies of this mutation (from both parents) are usually protected
against infection with HIV, although there have now been at least eight case reports where
infection occurred in people with two mutant CCR5 genes.4
The case was first reported in February 2008 as a poster presentation at the Conference on
Retroviruses and Opportunistic Infections (CROI) in Boston. The poster described an HIVpositive individual who had achieved an undetectable viral load on antiretroviral therapy for
several years before being diagnosed with acute myeloid leukaemia. After radiation treatment
and chemotherapy failed to successfully treat the leukaemia, he underwent stem cell therapy by
having a bone marrow transplant.
Out of a total of 232 potential donors with the same HLA type (genetic markers that identify
cells as self and prevent the immune system from attacking them), one donor was also found to
have two copies of delta32 CCR5.

The man was asked to stop his antiretroviral therapy the day before his bone marrow transplant,
since doctors were concerned it might have interfered with his recovery from the procedure.
However, 68 days following the transplant, he was found to still have an undetectable viral load
in his blood and bone marrow. Follow-up tests 285 days later also found no virus in rectal fluids,
where the virus is often present.
The investigators were careful not to call this a cure in their poster presentation, instead
suggesting that this finding... encourages further investigations of the development of CCR5targeted treatment options. 5

A functional cure
In September this year, the Foundation for AIDS Research (amfAR) arranged a meeting between
German haematologist, Dr Gero Htter - who had found the donor and performed the stem cell
transplant - and ten experts in clinical AIDS, stem cell transplantation and HIV virology. Further
details of the case were reported in an article published on the amfAR website on 5 November. 6
The man had suffered a relapse of his leukaemia following his initial transplant and had required
a second transplant using the same donor. However, he continued to have no detectable signs of
HIV in his blood, bone marrow and rectum, and further investigations found no HIV in his
lymph nodes or brain.
To the limits of our ability to detect HIV, wrote amfARs senior scientific consultant, Dr
Jeffrey Laurence, it appears that the virus has been eradicated from his body. At the very least
this patient represents a functional cure: he is off all anti-HIV meds, has a normal T-cell count,
and exhibits no evidence of virus. 7 However, the amfAR experts have arranged to examine
further specimens from the patient, since they believe the distinct possibility remains that HIV
has not been totally eradicated from his body.
The story was then picked up in the Wall Street Journal 8 on 7 November, and press interest grew
so great that Dr Htter and his colleagues at the Charit Clinic for Haematology and Oncology in
Berlin held a press conference on 12 November, resulting in global coverage of the case.

Limiting factors
There is no doubt that the case is remarkable, even if experts are not satisfied that HIV has been
completely and permanently eradicated. However, it is unlikely to be repeatable due to several
important limiting factors:

The number of potential donors is limited, since less than 1% of individuals in parts of
the Middle East, Europe and Asia (and none in Africa, Asia and South America) have two
copies of delta32 CCR5.9 In addition, there are more than 100 HLA types. Taken
together, the pool of potentially matching donors is very shallow indeed.

Bone marrow transplants are expensive (costing up to US$250,000 according to amfAR),

and result in a 10 to 30% mortality rate. Even Dr Htter admits that they are so dangerous

that "they can't be justified ethically" in anything other than life-threatening situations
like late-stage leukaemia. 10

The patient received immunosuppressive treatment for two years after the transplant.
Some experts think this has played a role in the failure of HIV to return.

However, this case report may aid ongoing research into treatments, such as gene therapy, that
seek to eradicate HIV - although cost and safety issues are likely to continue to be limiting
factors for the foreseeable future.

References
1.

Can HIV be cured? ATU 153, January/February 2006.

2.

Huzicka I Could bone marrow transplantation cure AIDS? Medical Hypotheses 52 (3): 247257, 1999.
3.

Avettand-Fenoel V et al. Failure of bone marrow transplantation to eradicate HIV reservoir

despite efficient HAART. AIDS 21 (6):775786, 2007.
4.

Sheppard HW HIV-1 infection in individuals with the CCR5-Delta32/Delta32 genotype:

acquisition of syncytium-inducing virus at seroconversion. JAIDS 29(3):307-13, 2002.
5.

Htter G et al. Treatment of HIV-1 infection by allogeneic CCR5-32/32 stem cell

transplantation: a promising approach. Fifteenth Conference on Retroviruses and Opportunistic
Infections, Boston, abstract 719, 2008.
6.

Laurence J A First Step Toward a Cure for AIDS? Novel Procedure Appears to Have
Eliminated HIV. The Foundation for AIDS Research. 5 November, 2008.
http://www.amfar.org/cgi-bin/iowa/programs/resrch/record.html?record=71
7.

Laurence J A first step toward a cure for AIDS? Novel procedure appears to have eliminated
HIV. amfAR, November, 2008. http://www.amfar.org/cgi-bin/iowa/programs/resrch/record.html?
record=71
8.

Schoofs M A doctor, a mutation and a potential cure for AIDS. Wall Street Journal. 7
November, 2008. http://online.wsj.com/article/SB122602394113507555.html
9.

Martinson JJ et al. Global distribution of the CCR2-64I/CCR5-59653T

HIV-1 disease-protective haplotype. AIDS 14:483-489, 2000.

10.

Harrell E Can a bone-marrow transplant halt HIV? Time, 13 November 2008.

http://www.time.com/time/health/article/0,8599,1858843,00.html?imw=Y

The startling case of an AIDS patient who underwent a bone marrow transplant to treat
leukemia is stirring new hope that gene-therapy strategies on the far edges of AIDS
research might someday cure the disease.
The patient, a 42-year-old American living in Berlin, is still recovering from his leukemia
therapy, but he appears to have won his battle with AIDS. Doctors have not been able to
detect the virus in his blood for more than 600 days, despite his having ceased all
conventional AIDS medication. Normally when a patient stops taking AIDS drugs, the
virus stampedes through the body within weeks, or days.

Sixten Koerper
Dr. Gero Htter isn't an AIDS specialist, but he 'functionally cured' a patient, who shows
no sign of the disease.
"I was very surprised," said the doctor, Gero Htter.
The breakthrough appears to be that Dr. Htter, a soft-spoken hematologist who isn't an
AIDS specialist, deliberately replaced the patient's bone marrow cells with those from a
donor who has a naturally occurring genetic mutation that renders his cells immune to
almost all strains of HIV, the virus that causes AIDS.
The development suggests a potential new therapeutic avenue and comes as the
search for a cure has adopted new urgency. Many fear that current AIDS drugs aren't
sustainable. Known as antiretrovirals, the medications prevent the virus from replicating
but must be taken every day for life and are expensive for poor countries where the
disease runs rampant. Last year, AIDS killed two million people; 2.7 million more
contracted the virus, so treatment costs will keep ballooning.
While cautioning that the Berlin case could be a fluke, David Baltimore, who won a
Nobel prize for his research on tumor viruses, deemed it "a very good sign" and a virtual
"proof of principle" for gene-therapy approaches. Dr. Baltimore and his colleague,
University of California at Los Angeles researcher Irvin Chen, have developed a gene

therapy strategy against HIV that works in a similar way to the Berlin case. Drs.
Baltimore and Chen have formed a private company to develop the therapy.
Back in 1996, when "cocktails" of antiretroviral drugs were proved effective, some
researchers proposed that all cells harboring HIV might eventually die off, leading to
eradication of HIV from the body -- in short, a cure. Those hopes foundered on the
discovery that HIV, which integrates itself into a patient's own DNA, hides in so-called
"sanctuary cells," where it lies dormant yet remains capable of reigniting an infection.
But that same year, researchers discovered that some gay men astonishingly remained
uninfected despite engaging in very risky sex with as many as hundreds of partners.
These men had inherited a mutation from both their parents that made them virtually
immune to HIV.
The mutation prevents a molecule called CCR5 from appearing on the surface of cells.
CCR5 acts as a kind of door for the virus. Since most HIV strains must bind to CCR5 to
enter cells, the mutation bars the virus from entering. A new AIDS drug, Selzentry, made
by Pfizer Inc., doesn't attack HIV itself but works by blocking CCR5.
About 1% of Europeans, and even more in northern Europe, inherit the CCR5 mutation
from both parents. People of African, Asian and South American descent almost never
carry it.
Dr. Htter, 39, remembered this research when his American leukemia patient failed
first-line chemotherapy in 2006. He was treating the patient at Berlin's Charit Medical
University, the same institution where German physician Robert Koch performed some
of his groundbreaking research on infectious diseases in the 19th century. Dr. Htter
scoured research on CCR5 and consulted with his superiors.
Finally, he recommended standard second-line treatment: a bone marrow transplant -but from a donor who had inherited the CCR5 mutation from both parents. Bone marrow
is where immune-system cells are generated, so transplanting mutant bone-marrow
cells would render the patient immune to HIV into perpetuity, at least in theory.
There were a total of 80 compatible blood donors living in Germany. Luckily, on the 61st
sample he tested, Dr. Htter's colleague Daniel Nowak found one with the mutation from
both parents.
To prepare for the transplant, Dr. Htter first administered a standard regimen of
powerful drugs and radiation to kill the patient's own bone marrow cells and many

immune-system cells. This procedure, lethal to many cells that harbor HIV, may have
helped the treatment succeed.
The transplant specialists ordered the patient to stop taking his AIDS drugs when they
transfused the donor cells, because they feared the powerful drugs might undermine the
cells' ability to survive in their new host. They planned to resume the drugs once HIV reemerged in the blood.
But it never did. Nearly two years later, standard tests haven't detected virus in his
blood, or in the brain and rectal tissues where it often hides.
The case was presented to scientists earlier this year at the Conference on
Retroviruses and Opportunistic Infections. In September, the nonprofit Foundation for
AIDS Research, or amFAR, convened a small scientific meeting on the case. Most
researchers there believed some HIV still lurks in the patient but that it can't ignite a
raging infection, most likely because its target cells are invulnerable mutants. The
scientists agreed that the patient is "functionally cured."
Caveats are legion. If enough time passes, the extraordinarily protean HIV might evolve
to overcome the mutant cells' invulnerability. Blocking CCR5 might have side effects: A
study suggests that people with the mutation are more likely to die from West Nile virus.
Most worrisome: The transplant treatment itself, given only to late-stage cancer
patients, kills up to 30% of patients. While scientists are drawing up research protocols
to try this approach on other leukemia and lymphoma patients, they know it will never
be widely used to treat AIDS because of the mortality risk.
There is a potentially safer alternative: Re-engineering a patient's own cells through
gene therapy. Due to some disastrous failures, gene therapy now "has a bad name,"
says Dr. Baltimore. In 1999, an 18-year-old patient died in a gene therapy trial. Even
one of gene therapy's greatest successes -- curing children of the inherited "bubble boy"
disease -- came at the high price of causing some patients to develop leukemia.

Gene therapy also faces daunting technical challenges. For example, the therapeutic
genes are carried to cells by re-engineered viruses, and they must be made perfectly
safe. Also, most gene therapy currently works by removing cells, genetically modifying
them out of the body, then transfusing them back in -- a complicated procedure that
would prove too expensive for the developing world. Dr. Baltimore and others are
working on therapeutic viruses they could inject into a patient as easily as a flu vaccine.
But, he says, "we're a long way from that."
Expecting that gene therapy will eventually play a major role in medicine, several
research groups are testing different approaches for AIDS. At City of Hope cancer
center in Duarte, Calif., John Rossi and colleagues actually use HIV itself, genetically
engineered to be harmless, to deliver to patients' white blood cells three genes: one that
inactivates CCR5 and two others that disable HIV. He has already completed the
procedure on four patients and may perform it on another.
One big hurdle: doctors can't yet genetically modify all target cells. In theory, HIV would
kill off the susceptible ones and, a victim of its own grim success, be left only with the
genetically engineered cells that it can't infect. But so far that's just theory. All Dr. Rossi's
patients remain on standard AIDS drugs, so it isn't yet known what would happen if they
stopped taking them.
In 1989, Dr. Rossi had a case eerily similar to the one in Berlin. A 41-year-old patient
with AIDS and lymphoma underwent radiation and drug therapy to ablate his bone
marrow and received new cells from a donor. It is not known if those cells had the

protective CCR5 mutation, because its relation to HIV hadn't been discovered yet. But
after the transplant, HIV disappeared from the patient's blood. The patient died of his
cancer 47 days after the procedure. Autopsy tests from eight organs and the tumor
revealed no HIV.
Write to Mark Schoofs at mark.schoofs@wsj.com
Corrections & Amplifications
The Foundation for AIDS Research, which uses the acronym amFAR, is the name of the
nonprofit group cited in this article. The name of the group was incorrectly given as the
American Foundation for AIDS Research.
HIV eradication unlikely following bone marrow transplantation
How HIV works
Edwin J. Bernard
Published: 24 April 2007

The first published report of the HIV eradication potential of a bone marrow transplant in an
individual on highly active antiretroviral therapy (HAART) has concluded that eradication is
unlikely utilising this method. The report is published as a letter in the March 30th issue of the
journal AIDS.
Currently available anti-HIV drugs may be able to reduce HIV to 'undetectable' levels in the
blood, but they cannot remove HIV's genes that are integrated in the DNA of our own cells.
Although scientists have been working on eradicating HIV from the body for more than two
decades, and knowledge is increasing incrementally, their work has ultimately been
disappointing.
One possible avenue considered promising in the pre-HAART era was bone marrow
transplantation. Between 1982 and 1996, reports of over 30 bone marrow transplants in HIVpositive individuals with advanced disease were published. In some cases, individuals required
chemotherapy and radiation and subsequent bone marrow transplants for non-Hodgkin
lymphoma. In other cases researchers actively enrolled individuals with AIDS at a time when
there appeared to be no other options and replaced their bone marrow with those from healthy
transplanted donors in order to attempt to repopulate the individuals immune system with
healthy, HIV-free blood cells.
Although most died due to HIV- or transplant-related complications soon after the procedures,
two individuals were found to have undetectable HIV RNA and DNA levels in the weeks and
months following the procedures. A review of these reports, written in 1997, and published in
1999, suggested that bone marrow transplantation offered the tantalising possibility of a cure

for HIV. It suggested that utilising more potent anti-HIV drugs alongside pre-transplant chemoor radiation therapy might provide a more satisfactory outcome, since AZT monotherapy had
been used in most cases (Huzicka 1999).
Since then, however, other less toxic and/or invasive methods of HIV eradication have been
attempted, and many different kinds of studies are ongoing.
French investigators have now reported the first case of a bone marrow transplant in an HIVpositive individual on HAART. The individual, a young man who required a transplant to treat
monocytic acute myeloid leukaemia (AML) had achieved an undetectable viral load for 18
months before the transplant, and remained on HAART with a short interruption following
the transplant until his death 191 days post-transplant.
The investigators used ultra-sensitive methods to measure HIV DNA levels in the mans
peripheral blood mononuclear cells (PBMC). Before transplantation, HIV DNA was at 2.76 log10
copies/106 PBMC. After undergoing bone marrow ablation chemotherapy which destroyed his
own marrow and then a bone marrow transplant, the procedure was considered a success with
full restoration of blood cells after 19 days, and remission from AML confirmed at day 124.
Following the bone marrow transplant, blood plasma HIV RNA remained undetectable and HIV
DNA levels examined in more than a million PBMCs became undetectable (<2 log10 copies/106
PBMC), which, write the investigators, gave hope of a significant reduction of the reservoir,
indeed HIV remission.
However, the man experienced severe graft-versus-host disease (which is when the immune cells
from the donated marrow attack the body of the transplant patient, often affecting skin, eyes,
stomach and intestines) which was only partially controlled via immunosuppressive drugs.
At 114 days post-transplant, HAART was interrupted for three weeks due to suspected toxicity,
and sixteen days after HAART interruption both HIV RNA (4.61 log10 copies/ml) and HIV DNA
(2.50 log10 copies/106 PBMC) became detectable again.
Phylogenetic analysis of four plasma viral strains (two in 2003, and two after the transplant)
suggested that two totally different HIV quasispecies were in circulation before and after the
bone marrow transplant, which, write the investigators, confirmed that the viral reservoir
previously constituted was not eradicated... Unfortunately the HIV-1 replication recovery a few
days after HAART interruption unambiguously showed the persistence of an infectious viral
residual reservoir.
They conclude, despite the use of intensive pretransplant cytoablative conditioning with
chemotherapy combined with 18 months of potent effective HAART before [bone marrow

transplant] (contrary to zidovudine alone used in cases described before 1996), the goal of HIV
eradication was not achieved for this patient.
References

Avettand-Fenoel V et al. Failure of bone marrow transplantation to eradicate HIV reservoir

despite efficient HAART. AIDS 21 (6):775786, 2007.
Huzicka I. Could bone marrow transplantation cure AIDS?: review. Medical Hypotheses 52 (3):
247-257, 1999.
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Bone marrow transplants to cure HIVa long and troubled history

Sean Hosein
CATIE News: December 12, 2008

Widely available in most high-income countries, highly active antiretroviral therapy (HAART)
can put AIDS into remission and greatly prolong the life of HIV positive people. However,
HAART has not cured HIV infection. Despite this setback, researchers struggle to find a cure.

When AIDS was first recognized in the 1980s, researchers noted that many patients had a
profound weakness in their immune system because of the presence of overwhelming infections.
In that decade, many studies were done with so-called immune boosters but none proved to
provide consistent benefit. Still, at least the recognition of the immune deficit meant that
researchers knew the immune system needed help. This led some scientists to consider
transplanting bone marrow from healthy HIV negative people into HIV positive people. The hope
was that the transplanted tissue would form new blood and immune cells and restore the health of
the recipient, whose immune cells were depleted.

In 1983, researchers attempted the first bone marrow transplant (BMT) to help restore immunity
in a man with HIV-related illness. Sadly, the attempt failed and so did a subsequent try in another
man with HIV. A BMT in 1984 in another HIV positive man resulted in a brief improvement
before he died.

Add AZT
By 1989, with more tools at their disposal, researchers were becoming more creative in trying to
cure HIV/AIDS. One team tested its idea on an HIV positive man who had cancer. Researchers
would first wipe out the patients bone marrow with radiation and, in subsequent experiments on
other people, sometimes also chemotherapy. This would then be followed by intravenous doses of
the first anti-HIV drug, AZT (zidovudine, Retrovir), prior to transplantation. Unfortunately, the
first patient died from a relapse of cancer nearly two months after the transplant. Using the
technology available at the time, researchers could not detect any HIV in the man. This stimulated
further research using BMT in an attempt to cure HIV.

In an experiment on 16 HIV positive people without cancer, American researchers used intensive
doses of AZT combined with bone marrow transplants and regular infusions of lymphocytes from
their HIV negative twins. This failed to rebuild the recipients immune systems and cure them of
HIV.

The big picture

Between 1982 and 1996, at least 32 attempts to cure HIV infection or restore immunity with
BMT were reported. In only two cases (of all those for which detailed reports and long-term
monitoring were available) did researchers claim that HIV could not be detected. ( However, both
patients subsequently died from either recurring cancer or from a complication called graft versus
host disease (GVHD). This latter condition sometimes occurs when transplanted tissue attacks the
recipients body.

Technique is everything
The rigour of technique and technology used in the previously mentioned studies to try to find
HIV would be considered weak by todays standards. In the present era, a few research

laboratories have specialized in finding HIV in patient samples collected during eradication trials.
These labs conduct immense and time-consuming efforts to find HIV, sometimes culturing
millions of CD4+ T cells over months at a time. Using state-of-the-art techniques, in every case in
recent eradication experiments HIV has eventually been found. It is in this context that future
reports of a so-called cure must be evaluated.

The Berlin patient

A recent story in the Wall Street Journal written by award-winning author Mark Schoofs told the
tale of an HIV positive cancer patient in whom, after a BMT, doctors could no longer find HIV.
Newspaper headlines around the world interpreted this to mean that his HIV infection had been
cured. We urge our readers to be cautious when reading about this case and we will explain why
later in this report.
Case details
In 2006, a 40-year-old HIV positive man sought care at Berlins Charit Medical University
because of a diagnosis of leukemia. Despite taking HAART, his initial chemotherapy regimen
failed to cure the leukemia So for their second attempt at cancer treatment, his doctors tried
something novel. Before we explain their idea, some background information is necessary.
A rare mutation
HIV needs at least two receptors to enter and infect a cell. One receptor is called CD4+ and the
other is CCR5. Both of these receptors are commonly found on cells of the immune system. In
people of European ancestry, sometimes a rare mutation occurs whereby a persons immune
system apparently lacks the CCR5 receptor. This mutation is called delta-32. In Central Europe,
this mutation occurs in about 1% of people. And in northern Europe, this mutation is slightly
more common. However, in people whose ancestors came from Africa, Asia or South America,
this mutation is extremely rare.

So, the Berlin doctors undertook an experiment and recommended a BMT from a donor whose
cells lacked the CCR5 receptor. This meant that once the donated immune system grew in the
recipient, he too would have cells that did not have CCR5 receptors, at least in theory.

The transplant
The mans doctors blasted his body with intensive chemotherapy and radiation to try to wipe out
his bone marrow and immune system. Several days later he received the BMT, at which point he
stopped taking HAART because doctors were concerned that these drugs might affect the growth
of the new bone marrow. The patient also received transplant drugs to further suppress any
remnants of his immune system and to prevent the transplanted cells from attacking his body.

Results
After the transplant, technicians regularly tested his blood using a research assay that could assess
viral load with a lower limit of quantification of 15 copies. That is, the test could accurately count
down to as low as 15 copies/mL of blood. Two months after the mans BMT, the test could no

longer detect HIV. And five months after the BMT they could not detect HIV in samples from his
rectum.

Note that antibodies to HIV were initially not detected in his blood after his BMT but became
intermittently detectable several months later. It is possible that the intensive chemotherapy and
radiation could have wiped out HIV-infected cells. However, the Berlin doctors did not
apparently conduct the extensive tests that are used by laboratories that study HIV eradication.

What does it all mean?

The Berlin results are scientifically interesting and raise the possibility that one day, perhaps
using genetic therapy, HIV might be cured. However, for now it is far too early to describe this
case as cured. HIV could still be lurking deep inside the mans body, finding sanctuary in some
cell that perhaps has both CCR5 and CD4+ or even another receptor such as CXCR4. This other
co-receptor can be used by HIV to enter cells. So researchers need to be vigilant against the
possibility that the man has HIV-infected cells that have both CD4+ and one of these two
receptors: CCR5 or CXCR4. That will require much testing.

Note that BMTs in HIV do not usually have a good long-term outcomehistorically most
patients died from complications of the transplant or HIV, or, if they had cancer, the cancer
returned, causing death. The Berlin researchers need to monitor this man extensively for many
years before they can be certain about his HIV status.

The French outcomeHAART + BMT

Last year, French researchers reported the results of a BMT in an HIV positive teenager. He was
symptom-free with moderately elevated CD4+ counts until 2003, when he developed lymphoma.
He then began taking HAART and recovered from lymphoma, but in 2005 he developed another
cancerleukemia. Chemotherapy for this second cancer worked for a few months before he
relapsed. So his doctors proposed a BMT (from a donor without the rare delta-32 mutation). Like
many of the other cases we have described, his immune system was first wiped out with intensive
chemotherapy, followed by a BMT accompanied by transplant drugs to suppress any attacks his
new immune system might mount against his body. He continued to take HAART after the
transplant, except for brief periods of suspected toxicity. Tests several months after the BMT
showed that he had recovered from leukemia.

After the BMT, tests for HIV and infected cells in samples of tissue taken from the mans rectum,
throat and lymph nodes suggested that the virus had been cleared there. However, four months
after the transplant he had to interrupt HAART, and HIV and HIV-infected cells became
detectable again. This development suggests that HIV had not been eradicated. He later
developed intensive graft versus host disease as his new immune system attacked the skin and
intestines, despite the extensive use of transplant drugs to suppress such attacks. He then
developed complications from several infections and died six months after his transplant.

The French report is notable because unlike previous reports from the 1980s or early 1990s, when
AZT was the only anti-HIV agent used, the French used combination therapy or HAART.

Implications for people with HIV

The German findings are scientifically interesting yet not practical. People who have the delta-32
mutation are rare, and even more so among potential donors of bone marrow. So there is no way
that the German results will be repeated on a large scale and certainly not in low-income
countries where the HIV pandemic rages.

The good news is that the results of the German experiment provide hope that one day HIV might
be cured. It will certainly stimulate other researchers to try to repeat the experiment to confirm
the results. And one day, scientists might develop a genetic therapy that could make a persons
immune system resist HIV. It might also prompt other researchers to study wider use of drugs,
such as maraviroc (Celsentri, Selzentry), that block the CCR5 receptor, preventing HIV from
infecting cells. Maraviroc is approved for use as part of combination therapy for treatmentexperienced patients in Canada and other high-income countries.

Our next CATIE News story examines another potential therapy that claims to have wiped out
HIV.

Acknowledgement
We thank Andrew Badley, MD, PhD, (Mayo Clinic College of Medicine) for helpful discussions.

-Sean R. Hosein

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9. Han Y, Wind-Rotolo M, Yang HC, et al. Experimental approaches to the study of HIV-1
latency. Nat Rev Microbiol. 2007 Feb;5(2):95-106.

10. Htter G, Nowak D, Mossner M, et al. Treatment of HIV infection by allogenic CCR532/32 stem cell transplantation: a promising approach. In: proceedings and abstracts of the
15th Conference on Retroviruses and Opportunistic Infections, Boston, 3-6 February 2008. Poster
719.

11. Schoofs M. A doctor, a mutation and a potential cure for AIDS. Wall Street Journal. 7
November 2008.

12. Avettand-Fenoel V, Mahlaoui N, Chaix ML, et al. Failure of bone marrow transplantation to
eradicate HIV reservoir despite HAART. AIDS. 2007 Mar 30;21(6):776-7.

20081212

Can we create elite controllers?

Published: 01 November 2008

Is combination immunotherapy the future? ask Edwin J Bernard and Derek Thaczuk
Jump to

The search for elite controllers

Immunotherapy: giving the immune system a boost

Therapeutic vaccines: an alternative to lifelong treatment?

Isnt HIV treatment enough?

A new study in combination immunotherapy

Whats in the vaccine?

What is being used along with the vaccine, and why?

Taking part

The search for elite controllers

Not all immune systems are created equal. Without appropriate antiretroviral treatment, most
people who have been infected with HIV will progress towards more serious disease some
more slowly, others more quickly. However, about one-in-a-hundred HIV-positive people show a
natural ability to at least partially control HIV infection and really slow down disease
progression. These so-called long-term non-progressors are able to maintain close-to-normal
health, low viral loads, and high CD4 cell counts for up to three decades (so far), without the
need for treatment. In addition, some non-progressors, so-called elite controllers, are able to
maintain undetectable viral loads (i.e. below 50 copies/ml) without the use of antiretrovirals.
Research into long-term non-progression began in the early 1990s when researchers in San
Francisco realised that they had patients infected between 1978 and 1980, in the very earliest
phase of the epidemic, who were still healthy, with normal immune systems and very low levels
of HIV in their blood. The research,1 by Susan Buchbinder and colleagues caused excitement at
the 1993 International AIDS Conference in Berlin, and led to the establishment of other studies
around the world. It also led to an understanding that the phenomenon was more common than
expected.
If you talk to anyone who has a practice of 300 HIV patients, they will have [an elite
controller], noted Bruce Walker of Harvard University Medical School during the 2006 launch
of the HIV Elite Controllers Consortium, an international collaboration between researchers in
the United States, Canada, Europe and Australia.2
Naturally, there has been great interest in why some people are able to control their HIV for long
periods of time without antiretrovirals. Part of the reason may be due to the particular strain of
virus that person has been infected with. HIV has evolved into a wide variety of strains some
more potent, some less so. Infection with a wimpy strain of virus may mean it does less damage
and is more easily controlled by the immune system.
On the other hand, it may have something to do with characteristics of the infected person, rather
than the virus these are known as host factors. Professor Frances Gotch and her colleagues
from Imperial College, based at Londons Chelsea & Westminster Hospital, have identified a
number of long-term non-progressors and, together with several other groups of researchers
worldwide, have shown that there may be a genetic component to non-progression some
people may simply be lucky enough to have inherited a protective genetic make-up from their
parents.
For those lucky enough to be elite controllers, however, both factors wimpy virus and
inherited genes may apply.

Of course, we cannot pick and choose the virus we are infected with or the genes we are born
with. But Prof. Gotch and others are investigating what we might be able to learn from the more
genetically fortunate. Once we have identified the characteristics that keep non-progressors well,
the next question is whether it is possible to induce these characteristics in others.
Of most interest to us as immunologists, Prof. Gotch tells HTU, is the fact that many longterm nonprogressors have exceptionally good HIV-specific immune responses. Using
sophisticated technology to measure the quantity and quality of such HIV-specific cellular
immune responses, Prof. Gotch and her colleagues at Imperial College have found that their
group of long-term non-progressors show particularly high levels of CD8 killer cells as well as
high levels of effective CD4 T helper cells in the blood; together these seem able to keep the
levels of virus down.
'Killer' cells
While most people with HIV are well acquainted with their CD4 cells, which communicate with
other immune cells and co-ordinate the overall immune response, CD4s are actually just one of
many types of immune cells that play distinct but interlocking roles in fighting infections. CD8
cells, often overlooked, are also extremely important. CD8 cells, in addition to being 'killers', are
also able to act as 'suppressors' of viral replication. Killer CD8 cells destroy infected human
cells, sacrificing them in a bid to keep infection from spreading further.
Immunotherapy: giving the immune system a boost

It would obviously be more desirable to be a long-term non-progressor or even better, an elite

controller than to be entirely reliant on anti-HIV drugs for the rest of your life. While we do
not yet know whether this is realistically achievable for the majority of people with HIV,
immunotherapy studies may yield ways of delaying (or possibly even avoiding) the need for HIV
treatment hopefully without introducing prohibitive costs or complications of their own.
It seems possible that the necessary immune cells are not destroyed completely during chronic,
progressive infection, says Prof. Gotch. They may be present, yet unable to respond properly
to HIV. Immunotherapy aims to boost the body's own immune response especially the HIVspecific response that may be waiting for a boost.
One widely investigated therapy is a cytokine (a cellular messenger chemical) called interleukin2 (IL-2). In its natural form, as produced by immune cells, IL-2 stimulates the production and
maturation of CD4 cells. Clinical trials have shown that manufactured versions of IL-2
(Proleukin) can result in very dramatic increases in CD4 cell counts. However, despite ongoing
trials, there is still little evidence as to whether this translates into long-term clinical benefit. Still,
a recent study3 found that short courses of IL-2 (twice-daily injections over five days, every eight
weeks) may boost CD4 counts enough to delay the need for antiretroviral therapy by up to two

years. Results from two trials, ESPRIT and SILCAAT, expected next year, should help us
understand better the clinical benefits and risks of IL-2.
IL-2 has been around for more than a decade, but in a much more 21st century approach, several
researchers are experimenting with using a person's own immune cells, modified to create a more
effective response to HIV. In such autologous cell techniques, an individuals white blood cells
are reintroduced into the body after being treated in specific ways typically, by exposing the
cells to distinctive pieces of the virus that teach them to respond more robustly to HIV. While
still highly experimental and extremely costly several autologous cell techniques have so far
appeared safe and promising. Ultimate feasibility, effectiveness and safety of this technique
remains to be seen. 4,5
Therapeutic vaccines: an alternative to lifelong treatment?

Back in May 2006 (ATU 156), when we examined the fallout from the SMART study which
found that treatment interruptions are not a safe long-term treatment strategy, due to the
increased risk of serious illness and death when coming off HIV treatment compared to staying
on it we wondered whether this now means that triple drug combination HIV treatment is a
lifelong prospect. When we examined whether therapeutic vaccines were a viable alternative to
lifelong treatment we found short-lived early success and quite a few potential drawbacks.
In fact, when we interviewed two of the foremost HIV experts in the UK for our
January/February 2007 edition (ATU 163), both were definitely unenthusiastic about the
prospects of therapeutic vaccines making a difference to our treatment options. Therapeutic
vaccines wont work, said Dr Mike Youle, of Londons Royal Free Hospital. At best theyre
going to be mildly beneficial. Professor Brian Gazzard, of Chelsea & Westminster Hospital
agreed: I think the chances a therapeutic vaccine will have any impact is virtually zero.
Although there have been several promising candidates, including Remune (developed by Jonas
Salk, discoverer of the polio vaccine, and no longer being studied) and DemaVir (applied to the
skin, and still being studied) the best results so far have come from a team of French researchers
who created a cocktail of two therapeutic vaccines the ALVAC 1433 vaccine and HIV
lipopeptide plus IL-2. During viral-load-guided treatment interruptions (this study was done
before SMART) they found that the trial participants who received the therapeutic vaccine/IL-2
combination had, on average, viral loads ten times lower, and remained off anti-HIV drugs for
40% longer, than non-vaccinated patients. 6
However, earlier this year, an international collaboration reported that a similar therapeutic
vaccine ALVAC 1542 actually increased viral loads and reduced time off treatment - the
opposite of what had been hoped.7 The investigators believe these disappointing results may be
down to bad luck they found a higher proportion of natural non-progressors in the group that
didnt receive the vaccine than in the vaccine group. But it may also be possible that instead of

stimulating anti-HIV CD8 cells, which would kill HIV-infected cells, the vaccine mainly
stimulated the formation of HIV-specific CD4 cells which might only serve as targets for more
HIV replication.
Isnt HIV treatment enough?

Currently, the most commonly used immune boosting therapy is HIV treatment itself. Most
people who respond well to antiretroviral therapy have a dramatic increase in their CD4 count in
the first few months of treatment, followed by a more gradual rise during subsequent months.
This later phase is accompanied by improved function and restoration of a wider range of
immune responses. So why do we need a therapeutic vaccine?
Taking antiretroviral therapy does not normally rejuvenate the HIV-specific immune responses
needed to keep the virus under control [if you ever stop treatment], argues Professor Gotch.
Consequently, if the drugs are stopped or fail in some way, the levels of virus will rebound and
CD4 cell counts will plummet. She also argues that antiretroviral therapy is not available to at
least 70% of HIV-positive people in the developing world who require it, although some experts
wonder whether potentially expensive and complex combination immunotherapy could be a
realistic alternative for resource-limited settings.
A new study in combination immunotherapy

With these things in mind, and with lessons learned from past immunotherapy and therapeutic
vaccine studies, Prof. Gotch and her colleagues at the St Stephens AIDS Trust, Chelsea &
Westminster Hospital, and Imperial College, are about to start a Medical Research Councilfunded study (called IMIRC1003) in HIV-positive people who are on successful HIV treatment
(defined as viral loads below 50 copies/ml and CD4 T-cell counts over 400 cells/mm3) which will
combine several new immunotherapeutic approaches.
They will use a new kind of DNA vaccine boosted with several different cytokines and hormones
(see below) in a strategic attempt to regenerate missing HIV-specific cellular immune responses.
Our goal, says Prof. Gotch, is to make chronically infected people act more like elite
controllers. Our hope is that, in the future, we may be able to take people off antiretroviral
therapy. She adds that the study has been reviewed and approved by GTAC8 (the Gene Therapy
Advisory Committee the ethical review panel for all research involving gene therapies in the
UK).
What is different about this study, compared to those in the past, is that this one combines several
different immune modulating cytokines and hormones with a therapeutic vaccine, notes Dr
Nesrina Imami, a colleague of Prof. Gotch who is working on the study. They have also thought
long and hard about the timing and dosage of each of the individual components. No consensus
has yet emerged concerning the optimal timing and dosing regimens of vaccines and cytokines,

Dr Imami tells HTU, but recent studies from ourselves and others have suggested that sustained
responses may be induced by:

Treating patients with antiretrovirals before CD4 T-cell counts fall below 200 cells/mm3.

Allowing reconstitution of CD4 T cells to a level equal or above 400 cells/mm3.

Inducing or reintroducing specific cellular and humoral (antibody) responses by priming

with vaccines representing a broad spectrum of antigens with novel adjuvants.

Increasing survival of vaccine responses through the administration of

cytokines/hormones.

Boosting memory responses with further immunisation.

Whats in the vaccine?

GTU [Gene Transport Unit]Multi-HIV B clade vaccine is produced by a small Finnish biotech
company, called FITBiotech. It is a DNA vaccine containing parts of HIVs genetic material (for
the geeks amongst you, these are: complete sequences of Rev, Nef, Tat, p17/p24 proteins, and an
epitope stretch of previously identified T cell epitopes in pol and env) and is designed to
stimulate cellular immune responses to HIV.
The vaccine has been evaluated in phase I/II clinical trials in Finland, both in healthy volunteers
and in anti-HIV-treated individuals, all of whom were infected with subtype B. In these studies
the vaccine was found to be safe.
Initial results from a phase II study9 of 60 treatment-nave individuals in South Africa (all of
whom were infected with subtype C) were presented last month at the AIDS Vaccine 2008
meeting in Cape Town. The participants had an average CD4 count of 560 cells/mm3 and an
average viral load of 41,000 copies/ml. A total of 20 participants received 0.5mg of the vaccine
injected under the skin, 20 received 1mg injected into the muscle, and 20 received a placebo (a
fake vaccine) at the start of the study, and one and three months later. These were then boosted
after 19 and 20 months with two more injections at double the initial doses. None took HIV
treatment during the study.
The investigators found that there were no vaccine-related serious adverse events although there
were some mild to moderate side-effects including bruising, itching and swelling at the injection
site. Interestingly, although the intramuscular injection resulted in stable CD4 counts (whereas
those on the placebo fell) and a small but significant (0.5 log) decrease in viral load compared to
those on placebo, increases in immune function were only observed in those receiving the underthe-skin vaccination (which is how the Chelsea & Westminster study will deliver the vaccine).

What is being used along with the vaccine, and why?

Along with the GTU vaccine, the study will be using the followingcytokinesandhormones
(chemicals which serve as triggers to immune functions):

Recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF).

This is a naturally occurring protein. When produced as a medicine by Novartis it is
known as sargramostim (brand name, Leukine), and is used to stimulate the production of
white blood cells.

Recombinant human IL-2, which is manufactured by Novartis under the brand name
Proleukin. IL-2 is normally produced in the body during an immune response and will be
used in this trial to boost the immune response to the vaccine.

Recombinant human growth hormone (rhGH) has mainly been used in studies to treat the
central weight gain that might accompany lipodystrophy, although recent studies10
suggest it may also have a beneficial effect on the immune system. The therapeutic form
of rhGH is produced by Serono International with the brand name Saizen.

The theory is that the vaccine will induce useful cellular immune responses able to recognise
HIV, and that such immune responses will be maximally enhanced by the use of this combination
of cytokines and hormones. Eventually, following a booster vaccination, this should result in a
long-lived pool of mature memory cells which mimic those seen in long-term non-progressors
and elite controllers and may be able to control HIV without the need for antiretroviral therapy
(although a treatment interruption to try to show this will not be part of this study).
Taking part

If you are considering taking part in this study, you should be aware that there may well be
drawbacks as well as potential benefits. As with most trials, some side-effects can be anticipated.
In particular, flu-like symptoms (such as fever, muscle aches and tiredness) may accompany
injections of IL-2 and GM-CSF, although the investigators will be using low doses of these
substances, which should help to minimise these symptoms (and which can be controlled by
taking ibuprofen or paracetamol). IL-2 may also sometimes cause mood changes, including
irritability, insomnia, confusion, or depression, and which can continue for several days after
they are stopped. Side-effects of rhGH can include headache, muscle pain, joint pain, salt and
water retention and rare instances of carpal tunnel syndrome (pain or tingling in the first three or
four fingers of the hand).
We cannot, of course, promise that the study will directly help the participants, says Prof.
Gotch, but we sincerely hope that the information we get from the trial may help improve
treatment for others with HIV in the future. In the absence of an effective preventative vaccine,

thousands of people are still becoming infected with HIV every day. It is essential to design
novel therapies to enable people living with HIV/AIDS to lead long and productive lives.
The authors would like to thank Professor Frances Gotch, Dr Nesrina Imami, and Dr Mark
Nelson of Chelsea & Westminster Hospital, London, for their contributions to this article.
References

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disease progression. Ninth International AIDS Conference, Berlin, abstract WS-BO3-2, 1993.
2. See: www.massgeneral.org/aids/hiv_elite_controllers.asp
3. Molina et al. Interleukin-2 (IL-2) therapy to prevent CD4 T-cell loss and defer HAART in
antiretroviral nave HIV-1 infected patients Interstart ANRS 119 trial. 17th International AIDS
Conference, Mexico City, abstract TUPDA105, 2008.
4. Routy et al. Autologous dendritic cells immunotherapeutic (Arcelis): tolerability and
immunogenicity in HIV-1-infected subjects treated with ART. 17th International AIDS Conference,
Mexico City, abstract TUPDA101, 2008.
5. Aronson et al. A clinical trial of CD4 zeta gene-modified T cell infusion with and without IL-2
in HIV infected participants. 17th International AIDS Conference, Mexico City, abstract
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8. See: www.advisorybodies.doh.gov.uk/genetics/gtac/
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