HIV immunity: rare gene differences offerhope for treatmentSeven years after the Berlin patient was cured of HIV, scientists are looking tonatural immunity through genetic variation to create vaccine and genetherapies

David Cox

Tuesday 12 May 2015 07.30 BST

I believe its possible to develop a mass-market single-shot treatmentfor 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 30years.

Its now seven years since Htter and his team at the Charit hospitalin Berlin performed a groundbreaking stem cell transplant on a 40year old HIV-positive patient, suering from leukaemia.Chemotherapy was used to destroy the cancerous cells in his immunesystem, replacing the tissue with bone marrow from a donor with anatural immunity to the virus. The patients name was Timothy RayBrown, and two years on when Browns body was found to beeradicated of any trace of the virus, the case of the Berlin patientwas hailed as the biggest breakthrough in the history of HIV research.

HIV attacks the body by binding to white blood cells, typically via areceptor called CCR5. Browns cure exploited a rare gene mutationwhich 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 accoladesand the acclaim died down, reality has slowly set in. Since Brown, sixmore HIV patients have been treated with similar transplants aroundthe world. None have survived longer than twelve months.

Instead of trapping and slowly eliminating the virus, some believethat disabling the CCR5 receptor simply provoked it to mutate andinvade cells via alternative receptors. But why did this happen inthose patients while Brown was cured? If we can understand this, wemay be able to translate his cure into something feasible for allpatients, Htter says.

Some researchers have suggested that the radiotherapy destroyed theHIV positive reservoir cells in Browns body or the transplanted donorcells may have triggered a graft versus host reaction, identifying theHIV positive cells as foreign and eliminating them. But in truth,exactly how the virus was completely eradicated from his systemremains a mystery.

Since 2009, donor centres screening for the CCR5 mutation haveemerged around Europe, but as well as providing no guarantees ofdestroying the virus, such transplants are unfeasible on a large scale.One potential solution is to combine radiation treatment withsustained gene therapy to disable a number of the common receptorsused 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 earlystage, Htter says. You can permanently disable a gene but this onlyworks if you change the DNA code. The risk is that you change theDNA strand at critical places where the replication and proliferation isencoded. If you accidentally manipulate the wrong part, theres a riskof inducing cancer.

It was 16 years ago that Professor Michael Farzan discovered thebenecial qualities of the CCR5 gene mutation at Harvard University.Now he believes hes close to developing an HIV vaccine based on thisform of natural immunity.

The vaccine binds to the virus and prevents it from getting insideyour cells in the rst place, he says. And if youre already infected, itcan prevent it from spreading to further cells and replicating. But thisisnt a cure. A cure would remove all evidence of the virus from thebody and we dont have that ability. But we think we can allow HIVpositive patients to reach a state called biologic remission, whichmeans they can live without drugs.

Previous vaccine attempts have aimed to stimulate the bodysimmune response. This time the approach is to simply blockade allknown cell receptors that the virus latches onto. While it is certainlycapable of nding new entry points, its unlikely to be as virulent.

Those strains of HIV are extremely rare so if it moves away from thecommon receptors, this will come with what we call a tness cost forthe virus, Farzan says. Because there are fewer strains, they are lessreplicative and transmissible.

While the CCR5 mutation has received the lions share of thespotlight, its also not the only form of natural immunity to HIV. Atthe University of Minnesota, Professor Reuben Harris is studyingcouples with mixed HIV status. These instances are extremelyinteresting because you have an infected person and their partnerwho remains HIV-negative despite many opportunities for the virus tobe transmitted, he says. By taking blood samples, we can playaround with the virus and work out what changes would need to bemade in order for it to infect cells from the partner. And from that wecan work out whats protecting them.

Theres a particular family of genes called APOBEC3 which producesantiretroviral enzymes, one of the bodys main defences against viralinfection. Harris has found that people with specic variations of thegene APOBEC3H produce stronger and more stable enzymes whichcan inhibit the replication of HIV. Having the right variant of this genemay make the likelihood of transmission much lower.

Understanding what happens at the point of transmission is the keyto successful intervention, Harris says. Its where the virus is mostvulnerable. When HIV is transmitted, its maybe one single virus or atmost a very small number. If those viruses dont take root, then theinfection cant get going and amplify.

Harris suggests that APOBEC3H could be the target of future genetherapy, aimed at making susceptible populations more resistant tothe virus. In particular, research has shown that few Caucasians havethe optimal version of this gene.

These enzymes are really powerful virus inhibitors and it may be

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possible to suppress infection completely by unleashing them to agreater extent, he says. The APOBEC3H gene could become part ofthe donor screening progress for future bone marrow transplants. If adonor 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 totalprotection from HIV. As well as mutating rapidly, the virus has its owncounter defences, producing a protein called viral infectivity factor(Vif) which tricks the body into destroying its own APOBEC3enzymes. But with genetics in your favour, the probabilities ofinfection are likely to be lower.

If you took 20 billion viruses, some of them would undoubtedly beresistant to APOBEC3H enzymes and maybe even to the CCR5deletion, Harris says. But at the point of transmission, youre onlyexposed so a few virus strains. So there we have the advantage andthe virus has the disadvantage, and any little genetic advantage wecan give people, then the odds are in their favour.

Harris is convinced that there are many other forms of naturalimmunity out there which remain undiscovered.

There are probably lots of dierent ways that people can resistinfection, he says. The CCR5 mutation may be one and APOBEC3Hmay be another. And these are just a few of many dierentmechanisms out there that we need to gure out. I guess its a perfectexample of why we dont want homogeneity in the human race. If wewere all the same then it would be too easy for a supervirus to sweepthrough and wipe us all out.