Gene
therapy – the process of manipulating human genetic material in order to slow
and stop disease and interfere with disease processes – is no longer science
fiction for people with HIV. While there is more to learn and the research is
new, gene therapy may lead to what is known as a ‘functional HIV cure’ by modifying
part of the body’s own genetic code in order to make cells resistant to HIV. If
a functional cure is successful, the damage HIV causes could be halted without
the use of antiretroviral drugs.
My
personal story intersects perfectly with the advent of HIV gene therapy. I have
been living with HIV almost half my life, since I was diagnosed in 1988, surviving
with a mixture of resilience and determination to live.
Clearly,
antiretroviral (ARV) drugs have kept me alive and relatively healthy. I was
always keen to benefit from what medicine could do for me, and enrolled in
several early-access programmes and clinical trials of unproven drugs in the
late ‘80s and ‘90s.
Back
then I didn’t have the choices we have today, with now more than two dozen antiretroviral
drugs available. As drugs were approved one at a time, many people added a new
drug to an older one they were taking, which we now understand leads to
resistance. I always managed to stay ahead of the latest treatments, but since
it was unclear how to best use the drugs in the early days of HIV, I developed
resistance to almost every drug and now have a fragile immune system with few
new treatment options in my future. Fortunately, the drugs were just useful
enough to keep my health stable, but until quite recently I never achieved an undetectable
viral load and my CD4 cells bottomed out at 30 cells/mm3. The good
news is that, thanks to careful monitoring, I never had an AIDS-defining
infection.
I’m
now thriving. In 2008 I was finally able to combine two new antiretroviral
drugs that I had never tried before and reached undetectable HIV levels,
remaining that way since then. But my CD4 cells remained stubborn, rarely
crossing over the 200 cells/mm3 benchmark that defines AIDS in the
US, where I live.
I
have never been reticent about participation in clinical trials. Back in the ‘90s,
many people enrolled in studies just to get access to the latest drugs. I even
signed up for a study looking at thymus transplantation, which involved opening
my abdomen in a surgical procedure. People thought I was brave, if not a bit
crazy, but I have always felt that if I sat around and waited for the research
to prove successful, I would not survive.
My
personal story intersects perfectly with the advent of HIV gene therapy. I have
been living with HIV almost half my life, since I was diagnosed in 1988, surviving
with a mixture of resilience and determination to live.
Since
the days of ACT UP Golden Gate when, as a dedicated treatment activist, I was
arrested seven times in civil disobedience protests, I have sought immune-based
therapies and advocated for research that would focus on CD4 cells, HIV’s
target. Until recently there have been no successful immune-based therapy
studies to restore the CD4 cells in people with HIV. Two huge and expensive
efforts, the ESPRIT2 and SILCAAT3 trials, used a
synthetic version of interleukin-2 (IL-2), a naturally occurring protein also
known as T-cell growth factor. Unfortunately, despite early promise in boosting
important CD4 cells in trial participants, the treatment was found to be
difficult to tolerate and in the end, ineffective. Before the study results
came out, a doctor prescribed IL-2 for me. My CD4 count increased to over 600
cells/mm3 from a low of 140 cells/mm3, but in about a
month they dropped back to where I started. Another failed treatment attempt!
But
today I may have hope for restoration of my immune system, or at the very least
an expansion of CD4 cells. In 2009, I visited the Quest Research Clinic in San
Francisco and met with Jay Lalezari, MD, a research physician I have known
since the days of ACT UP Golden Gate.
He
told me that his clinic was testing a new gene therapy technology called SB728.
This is an enzyme from a family called zinc finger nucleases (ZFNs), which
could theoretically make CD4 cells resistant to HIV. The ZFNs are like tiny
molecular ‘scissors’ that cut out the CCR5 gene. This gene provides CD4 cells with
the CCR5 molecule, a ‘co-receptor’ protein that studs CD4 cell surfaces and
which is an essential anchoring point for the most common form of HIV. Cells
without the CCR5 co-receptor are effectively protected from HIV infection.
After
speaking with several treatment activists and researchers including Dr Jay, as
he is affectionately known, I decided the risk was low and wanted to try it
out. So far, six months later, it appears the strategy is at the least safe, if
not showing some positive effects.
I
enrolled in the study in the summer of 2010 and flew to Los Angeles for what is
called an apheresis procedure. In this, you get hooked up to an oven-sized
machine that removes blood and separates the cell types within it. First, an
intravenous needle was placed in each of my arms; blood was removed from one
arm and infused into the machine where it separated out the white cells
(including CD4 cells). The remaining red blood cells were then replaced into my
other arm. By the end of the procedure, only a small infusion bag a quarter
full of blood had been taken from my arm. The apheresis was effortless and I
was out of the clinic in a few hours.
The
simplest explanation of the next steps of the process goes something like this.
My white blood cells were sent to the laboratory and the CD4 cells were
separated, made to replicate so there were more of them, and processed with the
zinc finger nucleases to remove their CCR5 gene. The ZFNs were delivered to my
cells inside the test tube enclosed in something called an adenovirus vector:
the hollowed-out shell of a common cold virus, which is able to enter cells and
deliver its contents to a cell’s nucleus, but cannot cause an infection.
The
newly modified cells were then frozen, sent to the study clinic, thawed and
infused back into my arm – four billion of them. I experienced no side-effects
during the 30-minute infusion.
My
own results have been quite exciting given my lacklustre treatment history. My
CD4 cell count doubled from 230 to 560 cells/mm3. Now, six months
later, my CD4 cells have remained at the higher level and I feel better than
ever. I have had virtually no long-term side-effects, though I have had to
endure extensive blood tests to follow up on my blood results.
Also,
and less comfortably, the study has required rectal biopsies to see if the
manipulated cells ‘traffic’ to the gut. This is important as it shows that the
modified cells are acting exactly like other immune cells and successfully
competing with them. It is also potentially exciting, since it is through
CCR5-bearing cells in the mucous membranes of the genital and digestive systems
that most people are infected with HIV. I have had about six 30-minute biopsy
procedures, cutting 20 tissue samples from inside my sigmoid colon each time.
The biopsies are relatively painless, save the amount of gas that’s pumped in
the colon so the doctor can remove the tissue with a tiny instrument. I have
not learned the results of my own biopsies so far, but the other participants
are showing good results.
Manipulating
DNA, the genetic blueprint, through gene therapy can be risky but has been
safely studied in cancer and degenerative diseases. This is not the first HIV-related
gene therapy trial, but it is the first to show promise. Dr Lalezari recently
presented data from the study I enrolled in at the Conference on Retroviruses
and Opportunistic Infections (CROI) in Boston in February. He presented data on
SB728 in six men who have been living with AIDS for over twenty years.4
This first study proved the gene therapy concept,
and I experienced a CD4 boost, but there was never any danger of my HIV running
out of control as I remained on antiretrovirals. The second study will enrol
people who are not taking antiretroviral therapy
Dr
Jay told me: “The study has shown seven things: logistically we can effectively
get peripheral blood mononuclear cells [white cells inhabiting the blood] out
of the body; the cells can be modified; the infusion is safe; the participants
have shown an increase in CD4 cells; the cells persist and don’t die off; and
they traffic to the gut.
“The
final thing is that there is also normalisation of the CD4:CD8 ratio.”
This
is particularly significant, because nearly all people with HIV, even with high
CD4 counts, have about twice as many CD8 cells (the cells that kill off
virus-infected cells) as CD4 cells (which direct a lot of the traffic of the
immune system). In HIV-negative people the situation is the opposite, with
twice as many CD4 as CD8 cells. Renormalising the CD4:CD8 ratio may imply that
my immune system has been ‘reset’ to resemble one a bit more like that of an
HIV-negative person.
Dr
Jay continues: “The key task lies in whether we can use the technique to
influence viral loads. We have almost completely enrolled a 14-patient trial
looking at this question.” This first study proved the gene therapy concept,
and I experienced a CD4 boost, but there was never any danger of my HIV running
out of control as I remained on antiretrovirals. The second study will enrol
people who are not taking antiretroviral therapy to answer the bigger question
of whether giving people a proportion of cells that are immune to HIV infection
will reduce the available pool of cells that can be infected, reduce viral
replication, and cause viral load to go down.
If
you were able to manage that trick so well it drove down viral load to an
undetectable level, then you might have your functional cure of HIV.
Even
though my study was small, five of the six participants had an average increase
of 200 CD4 cells/mm3 in one year of follow-up after the infusion.
There were no adverse events in the trial. One participant did not respond to
the new cells – most likely because they had a very low CD4 count to begin
with, or possibly because the adenovirus vector did not ‘take’ in enough cells.
Dr
Jay’s team showed that 25% of the total donated cells lacked the CCR5
co-receptor and that, after re-infusion, from 3 to 6% of those cells were
present after three months.
That
may not sound like a high proportion. However, the overall expansion of CD4
cells was high in all but one person and the fact that the CD4 cells reached
the gut shows that they can access one of HIV’s most important ‘hiding places’.
Furthermore, the hope is that, in a person not on HIV treatment, the proportion
of healthy, replicating CD4 cells without CCR5 may grow in time as cells with
the co-receptor are killed off by HIV.
The
motivation for this approach in CCR5-deleted cells came from the successful
treatment of Timothy Ray Brown, also known as the ‘Berlin patient’, which HTU covered earlier this year (see Towards a Cure for All, part 1 in issue
203). Brown, living with AIDS and leukaemia, received a bone marrow transplant
from a donor with CD4 cells naturally lacking the CCR5 receptor.
Five
years later, I met Brown in San Francisco. He is considered cured of HIV, and
the leukaemia is in remission. His case has spawned a new wave in HIV research,
including disruption of the CCR5 gene. The experiments thus far have not found
the cure for HIV, but answer important questions to further the research. It’s
truly an exciting time in HIV research.
I
will now visit the clinic to be monitored every month for six more months, and
then the study will be complete. As I look back on my treatment history I am
positive that the zinc finger experiment may allow me to restore my immune
system, perhaps reducing inflammation – the source of many non-AIDS-related
complications like cancer and heart disease. I already see an improvement in
the constant respiratory infections I used to get before I entered the study.
But best of all, I hope that one day I may be
able to stop antiretroviral drugs by being infused once a year with such gene
therapy techniques. Over the course of 22 years of taking meds, it’s yet
another risk that appears to have paid off.