HIV immunity: rare gene differences offer

hope for treatment

Seven years after the Berlin patient was cured of HIV, scientists are looking to
natural immunity through genetic variation to create vaccine and gene
therapies
David Cox
Tuesday 12 May 2015 07.30 BST

I believe its possible to develop a mass-market single-shot treatment

for HIV, says Dr Gero Htter. If we can overcome a few problems,
our approach is closer to a complete cure than anything in the last 30
years.
Its now seven years since Htter and his team at the Charit hospital
in Berlin performed a groundbreaking stem cell transplant on a 40
year old HIV-positive patient, suering from leukaemia.
Chemotherapy was used to destroy the cancerous cells in his immune
system, replacing the tissue with bone marrow from a donor with a
natural immunity to the virus. The patients name was Timothy Ray
Brown, and two years on when Browns body was found to be
eradicated of any trace of the virus, the case of the Berlin patient
was hailed as the biggest breakthrough in the history of HIV research.
HIV attacks the body by binding to white blood cells, typically via a
receptor called CCR5. Browns cure exploited a rare gene mutation
which occurs in around 1% of the population, disabling this receptor,
and making these individuals almost immune to infection.
Htter appeared to have the perfect solution. But after the accolades
and the acclaim died down, reality has slowly set in. Since Brown, six
more HIV patients have been treated with similar transplants around
the world. None have survived longer than twelve months.

Instead of trapping and slowly eliminating the virus, some believe

that disabling the CCR5 receptor simply provoked it to mutate and
invade cells via alternative receptors. But why did this happen in
those patients while Brown was cured? If we can understand this, we
may be able to translate his cure into something feasible for all
patients, Htter says.
Some researchers have suggested that the radiotherapy destroyed the
HIV positive reservoir cells in Browns body or the transplanted donor
cells may have triggered a graft versus host reaction, identifying the
HIV positive cells as foreign and eliminating them. But in truth,
exactly how the virus was completely eradicated from his system
remains a mystery.
Since 2009, donor centres screening for the CCR5 mutation have
emerged around Europe, but as well as providing no guarantees of
destroying the virus, such transplants are unfeasible on a large scale.
One potential solution is to combine radiation treatment with
sustained gene therapy to disable a number of the common receptors
used by the virus, but there is still some way to go to prove this is safe.
Gene therapy has its own risks and current trials are at a very early
stage, Htter says. You can permanently disable a gene but this only
works if you change the DNA code. The risk is that you change the
DNA strand at critical places where the replication and proliferation is
encoded. If you accidentally manipulate the wrong part, theres a risk
of inducing cancer.
It was 16 years ago that Professor Michael Farzan discovered the
benecial qualities of the CCR5 gene mutation at Harvard University.
Now he believes hes close to developing an HIV vaccine based on this
form of natural immunity.
The vaccine binds to the virus and prevents it from getting inside
your cells in the rst place, he says. And if youre already infected, it
can prevent it from spreading to further cells and replicating. But this
isnt a cure. A cure would remove all evidence of the virus from the
body and we dont have that ability. But we think we can allow HIV
positive patients to reach a state called biologic remission, which
means they can live without drugs.

Previous vaccine attempts have aimed to stimulate the bodys

immune response. This time the approach is to simply blockade all
known cell receptors that the virus latches onto. While it is certainly
capable of nding new entry points, its unlikely to be as virulent.
Those strains of HIV are extremely rare so if it moves away from the
common receptors, this will come with what we call a tness cost for
the virus, Farzan says. Because there are fewer strains, they are less
replicative and transmissible.
While the CCR5 mutation has received the lions share of the
spotlight, its also not the only form of natural immunity to HIV. At
the University of Minnesota, Professor Reuben Harris is studying
couples with mixed HIV status. These instances are extremely
interesting because you have an infected person and their partner
who remains HIV-negative despite many opportunities for the virus to
be transmitted, he says. By taking blood samples, we can play
around with the virus and work out what changes would need to be
made in order for it to infect cells from the partner. And from that we
can work out whats protecting them.
Theres a particular family of genes called APOBEC3 which produces
antiretroviral enzymes, one of the bodys main defences against viral
infection. Harris has found that people with specic variations of the
gene APOBEC3H produce stronger and more stable enzymes which
can inhibit the replication of HIV. Having the right variant of this gene
may make the likelihood of transmission much lower.
Understanding what happens at the point of transmission is the key
to successful intervention, Harris says. Its where the virus is most
vulnerable. When HIV is transmitted, its maybe one single virus or at
most a very small number. If those viruses dont take root, then the
infection cant get going and amplify.
Harris suggests that APOBEC3H could be the target of future gene
therapy, aimed at making susceptible populations more resistant to
the virus. In particular, research has shown that few Caucasians have
the optimal version of this gene.
These enzymes are really powerful virus inhibitors and it may be

possible to suppress infection completely by unleashing them to a

greater extent, he says. The APOBEC3H gene could become part of
the donor screening progress for future bone marrow transplants. If a
donor has a stable version of APOBEC3H and the CCR5 mutation,
then they have a double shot at protection from infection.
Of course such forms of natural immunity can never provide total
protection from HIV. As well as mutating rapidly, the virus has its own
counter defences, producing a protein called viral infectivity factor
(Vif) which tricks the body into destroying its own APOBEC3
enzymes. But with genetics in your favour, the probabilities of
infection are likely to be lower.
If you took 20 billion viruses, some of them would undoubtedly be
resistant to APOBEC3H enzymes and maybe even to the CCR5
deletion, Harris says. But at the point of transmission, youre only
exposed so a few virus strains. So there we have the advantage and
the virus has the disadvantage, and any little genetic advantage we
can give people, then the odds are in their favour.
Harris is convinced that there are many other forms of natural
immunity out there which remain undiscovered.
There are probably lots of dierent ways that people can resist
infection, he says. The CCR5 mutation may be one and APOBEC3H
may be another. And these are just a few of many dierent
mechanisms out there that we need to gure out. I guess its a perfect
example of why we dont want homogeneity in the human race. If we
were all the same then it would be too easy for a supervirus to sweep
through and wipe us all out.
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Topics
Aids and HIV
Medical research
Genetics
Biology