Read our related feature: Could we be about to eliminate AIDS?
Read our related editorial: Ridding the world of AIDS
IMAGINE going into hospital with HIV and receiving a single treatment that knocks the virus on the head for good. That dream may come true sooner than we thought following a flurry of progress in gene therapy.
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The story begins with a man in Germany who last week was reported to be free of HIV following a bone marrow transplant. The donor was known to have two copies of a gene that prevents HIV from invading white blood cells. For the first time, it may be possible to eliminate the virus from the body, as opposed to simply keeping it in check with antiretroviral therapies (ART).
Meanwhile, other researchers announced this week that they are making progress by altering a patient鈥檚 own white blood cells to make them resistant to HIV. While still preliminary, these gene therapies could help more people with HIV than transplants could, as they don鈥檛 rely on finding that rare compatible person who also happens to have the right genome.
The continuing failure of vaccines against HIV, and the disadvantages of ART, including their high cost, their toxicity, the difficulties of distributing them to people in developing countries and the impracticality of taking them every day for life, make these one-shot gene therapies all the more exciting.
Word first surfaced last November that a man had been 鈥渃ured鈥� of HIV through a bone marrow transplant, but this wasn鈥檛 confirmed until last week, when the full results were published in The New England Journal of Medicine . 鈥淚t鈥檚 now almost exactly two years ago that we treated him, and the virus is nowhere to be seen,鈥� says Gero H眉tter of the Charit茅 University of Medicine in Berlin, head of the team that treated the man.
鈥淚t鈥檚 now almost exactly two years since we treated him and the virus is nowhere to be seen鈥�
H眉tter exploited a finding a decade ago that some individuals naturally defy HIV. It turned out that they had inherited two copies of a 鈥渄elta32鈥� mutation in a gene called CCR5, one from each parent. That mutation means CD4 white blood cells can鈥檛 make a protein on their surface that HIV uses as a 鈥渄oor handle鈥� to invade the cells, so the virus can鈥檛 get in.
Then, when a man with HIV developed leukaemia and needed a bone marrow transplant, H眉tter reasoned that it might be possible to treat his cancer and also give him an HIV-resistant immune system, since his own would be destroyed by chemotherapy anyway. The hunt was on to find a donor with two delta32 mutations. From 80 potentials, he found one. After the transplant, HIV-resistant cells took over the man鈥檚 immune system, 鈥渃uring鈥� him of HIV. 鈥淓very new immune cell that grew thereafter in the bone marrow had these deletions, and so was resistant,鈥� says H眉tter.
Spectacular as the results are, the prospects for repeating it are limited. Bone marrow donors are rare, and donors with two delta32 mutations even rarer. What鈥檚 more, giving a bone marrow transplant to someone who doesn鈥檛 have cancer raises ethical issues. Enter gene therapy 鈥� a way of mimicking the same result without a donor.
Sangamo Biosciences of Richmond, California, began the first human trial of a promising gene therapy last week. 鈥淭he German patient is the definitive proof that if you replace patients鈥� immune cells, it鈥檚 sufficient to protect the patient,鈥� says Philip Gregory of Sangamo.
Sangamo makes artificial versions of natural enzymes called zinc finger nucleases (ZFNs), which zero in on and disrupt any genes you choose 鈥� in this case the CCR5 gene, so that it stops making the HIV door-handle protein.
The company plans to take blood samples from 12 patients and extract the CD4 cells. It will then add a harmless virus to the cell carrying genes that code for the ZFNs. The altered CD4 cells produce the ZFNs, which sabotage the CCR5 gene. The ZFNs and the virus are then washed away and the genetically modified cells injected back into the patient.
Although such a patient will still have many CD4 cells infected with HIV, if the engineered cells don鈥檛 become infected they should replicate faster and live longer than the others, and eventually become the dominant CD4 cells. This is exactly what happened when Sangamo researchers gave HIV-infected mice altered CD4 cells.
Gregory says that in the long term, it might be even more effective to extract and modify a different type of cell, called CD34 cells. Since they are stem cells, they can become every type of white blood cell, so this would eventually make the patient鈥檚 entire immune system resistant to HIV, which would be closer to the German leukaemia patient鈥檚 experience.
However, Gregory points out that engineering stem cells, rather than CD4 cells, raises the dilemma of whether to make room for the altered stem cells by destroying the patient鈥檚 existing bone marrow cells, which is what happened in the patient in Germany.
However, it might be ethically problematic to destroy an HIV patient鈥檚 existing immune cells if they aren鈥檛 also a cancer patient awaiting chemotherapy, the worry is that if this isn鈥檛 done, the engineered cells simply won鈥檛 take.
Indeed, this may be what happened in another major gene therapy trial, which announced its first results last week (Nature Medicine, ).
Researchers led by Ronald Mitsuyasu of the University of California, Los Angeles, removed blood from 74 people with HIV, extracted their CD34 stem cells, and exposed the cells from half the patients to a placebo and cells from the rest of the group to his team鈥檚 treatment, before injecting them back into the volunteers.
Mitsuyasu鈥檚 team treated the extracted CD34 cells with a virus that carries a gene for a ribozyme, an enzyme that exclusively snips out a pre-selected piece of genetic material. The ribozymes are expressed when the cells are injected back into the volunteers. This doesn鈥檛 keep HIV out of the cells but should stop it replicating by snipping up the tat gene in any HIV that enters the cell. In other words, the virus is disabled rather than being refused entry.
Assessments of the patients, who temporarily came off their ARTs so that the therapy could be tested, were carried out regularly for up to two years after their cells were first removed.
There were some encouraging signs: viral levels were three times as low in people who received the treatment than in those who got the placebo, and the number of uninfected CD4 cells reached higher levels too.
However, overall the results are disappointing. The altered stem cells gradually disappeared instead of multiplying, and the therapy didn鈥檛 protect the patients anywhere near as effectively as their usual ART.
One possibility is that the newly implanted stem cells couldn鈥檛 take because the old immune system was taking up too much room. Another possibility may be that it is better to keep HIV out of cells altogether, rather than fight the virus once it has invaded. If this idea proves to be correct, it bodes well for Sangamo鈥檚 trial, even though it is with CD4 cells, not stem cells.
鈥淧erhaps it is better to keep HIV out of cells altogether, rather than fight the virus once it has invaded鈥�
Meanwhile, a third gene therapy for HIV is in the works, and it combines parts of both Sangamo鈥檚 and Mitsuyasu鈥檚 approach. John Rossi, director of the City of Hope Medical Center in Duarte, California, is testing it in four patients. His team uses viruses to load patients鈥� blood cells with three genes to defend them against HIV 鈥� one that prevents production of the CCR5 door handle, and two others to sabotage HIV, even if it does break in. Rossi loaded the genes into CD34 cells extracted from his patients and reinjected them and is now monitoring their progress.
All have low concentrations of HIV in their blood, but they鈥檙e all also still on their usual drugs. 鈥淲e might temporarily take them off ART if they鈥檙e agreeable to that,鈥� says Rossi. That would show if the gene therapy alone can protect them.
In the meantime, the best option for people with HIV is still ART, and the challenge is to get it to as many people as possible (see 鈥淗ow to eradicate AIDS鈥�). 鈥淎t present, neither bone marrow transplantation nor gene therapy has a role in standard management of patients,鈥� points out Kevin De Cock, director of HIV/AIDS at the World 91色情片 Organization.
But those looking to the future can take heart from the gene therapy techniques and the success of the bone marrow transplant in the patient from Germany. 鈥淚t鈥檚 such a boon to gene therapy, this patient,鈥� says Ed Berger of the National Institutes of 91色情片 in Bethesda, Maryland, who 10 years ago discovered the vital role the CCR5 gene plays in HIV infection.
Read our related feature: Could we be about to eliminate AIDS?
Read our related editorial: Ridding the world of AIDS
