David Cox
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
A scanning electron microscopic image of HIV. The potential vaccine binds to the virus and prevents it from invading cells Photograph: MedicalRF.com/Corbis
“I believe it’s possible to develop a mass-market single-shot treatment for HIV,” says Dr Gero Hütter. “If we can overcome a few problems, our approach is closer to a complete cure than anything in the last 30 years.”
It’s now seven years since Hütter and his team at the Charité hospital in Berlinperformed a groundbreaking stem cell transplant on a 40 year old HIV-positive patient, suffering 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 patient’s name was Timothy Ray Brown, and two years on when Brown’s 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. Brown’s 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.
Hütter 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,” Hütter says.
Some researchers have suggested that the radiotherapy destroyed the HIV positive reservoir cells in Brown’s 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,” Hütter 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, there’s a risk of inducing cancer.”
It was 16 years ago that Professor Michael Farzan discovered the beneficial qualities of the CCR5 gene mutation at Harvard University. Now he believes he’s 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 first place,” he says. “And if you’re already infected, it can prevent it from spreading to further cells and replicating. But this isn’t a cure. A cure would remove all evidence of the virus from the body and we don’t 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 body’s 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 finding new entry points, it’s 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 fitness cost for the virus,” Farzan says. “Because there are fewer strains, they are less replicative and transmissible.”
While the CCR5 mutation has received the lion’s share of the spotlight, it’s 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 what’s protecting them.”
There’s a particular family of genes called APOBEC3 which produces antiretroviral enzymes, one of the body’s main defences against viral infection. Harris has found that people with specific 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. “It’s where the virus is most vulnerable. When HIV is transmitted, it’s maybe one single virus or at most a very small number. If those viruses don’t take root, then the infection can’t 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, you’re 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 different 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 different mechanisms out there that we need to figure out. I guess it’s a perfect example of why we don’t 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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