The man who was cured of HIV
You may have recently heard of the first person to be cured of human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS) . Timothy Ray Brown was HIV-positive and also had acute myeloid leukemia, a cancer that affects white blood cells. To treat the leukemia, doctors first used radiation to kill virtually all of his white blood cells – a dangerous procedure since it is these cells that make up the immune system and protect us from disease-causing viruses and bacteria. A bone marrow transplant was then performed to give Brown the stem cells necessary to develop new white blood cells and eventually regain a healthy immune system. Doctors used this bone marrow transplant not only to treat Brown’s leukemia but to also tackle his HIV infection. HIV can infect some of the white blood cells that grow out of bone marrow. When choosing a bone marrow donor for Brown, doctors selected an individual who had a rare genetic mutation that prevents most strains of HIV from infecting their white blood cells. After receiving a successful transplant from this donor, Brown now has a new immune system full of HIV-resistant cells. Since his transplant he has not needed any anti-retrovirals, the medications used to treat HIV/AIDS, and still no HIV can be detected in his blood. Because Brown has been stably HIV-free for three years, doctors think that he is cured! But what does that mean for the 30 million other people  infected with HIV around the world? Is the fight against AIDS over? Definitely not – but this first cure may bring us closer to the end of an epidemic.
How can cells be HIV-resistant?
HIV mainly infects a special type of white blood cell, called a T cell, by interacting with two proteins that stick out from the T cell’s surface: a receptor and co-receptor. HIV first binds to its receptor protein, called CD4, to start the entry process whereby the virus gets into the cell . After binding to CD4, HIV then binds to one of two co-receptors, either CCR5 or CXCR4, to enter the cell. Just like people are different from each other, one HIV virus can be different from another. Most HIVs use CCR5 as the co-receptor that allows them to enter the T cell and cause infection. But interestingly, some people have a genetic mutation that prevents them from producing the CCR5 protein. These individuals don’t have any CCR5 on the surface of their T cells, meaning that most types of HIV cannot infect these cells. Since the bone marrow used for Brown’s transplant came from a person with such a mutation, HIV resistant T cells grew from the transplanted stem cells.
Figure 1. HIV Entry: HIV binds to its receptor, CD4, on the cell surface through the virus’ gp120 protein (left). The virus then binds to its co-receptor, either CCR5 or CXCR4 (center). Binding to the co-receptor allows the virus to fuse with the cell surface, and enter the interior of the cell to cause infection (right). (Image credit: National Institute of Allergy and Infectious Diseases)
People with the CCR5 mutation for HIV-resistance still produce CXCR4, the alternative co-receptor for HIV entry that can be used by some varieties of HIV. Therefore cells with a CCR5 deficiency can still be infected by rarer forms of HIV. Luckily for Brown, having immune cells without the CCR5 receptor has been enough to stop the virus in its tracks. HIV has not been detected in his blood for three years, leading doctors to clinically classify him as cured of HIV.
Can this treatment be used for other individuals?
A bone marrow transplant is a high-risk procedure. There are many possible complications, including graft versus host disease, where the new immune cells from the bone marrow (the graft) attack the cells in the patient’s body (the host). In addition, to prevent such attacks from taking place, transplant recipients must take medications to suppress the immune system, but this suppression leaves patients more vulnerable to the bacteria and viruses that the immune system usually keeps at bay. Furthermore, finding a bone marrow donor is very difficult – cells have molecules on their surfaces that prevent the immune system from attacking them. In order for a transplant to be successful, these self-identifying molecules on the surface of the donor’s cells much match the molecules on the surface of the recipient’s cells. Because of these limitations, it’s unlikely that we will be able to use bone marrow transplant as a large-scale cure for AIDS.
Gene therapy may be one way to apply the cure from Brown’s CCR5-deficient transplant more broadly. Labs have recently designed proteins, called zinc finger nucleases, which can modify the genes for CCR5 and CXCR4 [4,5]. These nucleases recognize and cut a specific DNA sequence within a gene. The cut is then mended by the system that cells use to repair DNA breaks. However, this repair system frequently makes errors that can cause changes, known as mutations, within the gene that was cut. These mutations will cause changes in the protein for which the gene encodes and will often prevent the protein from being produced. By cutting the CCR5 and CXCR4 genes with zinc finger nucleases, scientists can produce cells that don’t have either HIV co-receptor, thereby making the cells resistant to HIV infection.
One possible way to use these nucleases for treatment is to take white blood cells or bone marrow stem cells from a patient and treat them so that they will produce two different zinc finger nucleases, one to tackle each co-receptor. Once the nucleases are made in these cells, they will cut both the CCR5 and CXCR4 genes. These treated white blood cells or stem cells will give rise to immune cells lacking both CCR5 and CXCR4, making them resistant to the vast majority of HIVs. These resistant cells can then be transferred back into the patient. Since the cells come from the same person to whom they are transferred, there is no risk of graft versus host reactions. Yet this procedure is not risk-free. While we know that people can be healthy without the CCR5 protein, since individuals like the Brown’s bone marrow donor do not produce it, there is no known example of a person who does not produce CXCR4. Preventing its production may therefore have negative effects on health. Another concern is that in addition to cutting the genes for the HIV co-receptors, the nucleases may also cut within other genes. Introducing these cuts may mutate genes needed for cell survival. Phase I clinical trials aimed at assessing safety are currently underway for treatment of HIV/AIDS patients using the zinc finger nuclease against CCR5 .
Thankfully for Timothy Ray Brown, a carefully chosen bone marrow transplant cured him of HIV. However, such transplants are dangerous and the risks of CCR5 and CXCR4 gene therapies still need to be assessed. It’s fair to say that while we now have an example of an individual cured of HIV, we may not have THE cure for HIV infection yet. However, we hope that the studies discussed above may bring us closer to a safe and effective treatment option that can be made accessible to people around the world who live with HIV/AIDS.
Jamie Schafer is a PhD student in Virology at the Harvard Graduate School of Arts and Sciences.
Meanwhile in Pretoria something unexpected happened:
Anti-AIDS gel also boosts sexual pleasure
Pretoria, June 15: South African scientists, who launched a 24-month trial to confirm the efficacy of a microbicide gel that would reduce the risk of women getting HIV, have found an unexpected spin-off – it also boosts sexual pleasure.
Wits professor Helen Rees, of the university”s reproductive health andHIV institute, said the R300m trial would involve about 2,200 sexually active women at seven locations countrywide.
The Tenofovir gel study – known as Follow-on African Consortium for Tenofovir Studies (Facts) study – would be a follow-up to the Caprisa 004 study, which showed that a highly consistent use of the microbicide by womenresulted in a 59 percent reduction in the risk of HIV infection.
Rees said during a previous study involving another gel – that proved unsuccessful in the fight against HIV – participants had noted the gel improved their sexual pleasure.
“One of the big messages we got, was many women said ‘We liked this’, News24.com quoted her as saying.
Most of the feedback during that study had come from women in their menopause. If the gel proved successful, the sexual pleasure factor could be a potential marketingoption, she said.
But while sexual pleasure might be a positive spin-off, the primary focus of the Facts study would be seeing if it backed up the Caprisa 004 study, which involved a smaller sample of women at only two locations in KwaZulu-Natal.
The Facts study would see the participants, aged between 18 and 30, using the gel 12 hours before intercourse and within 12 hours after intercourse.
The results of the study were expected to be released by the end of 2013. (ANI)
1. “Man appears free of HIV after stem cell transplant” <http://articles.cnn.com/2009-02-11/health/health.hiv.stemcell_1_cell-transplant-ccr5-cd4?_s=PM:HEALTH>
2. “Joint United Nation Program on HIV/AIDS” <http://www.unaids.org/en/>
3. “HIV Structure and Life Cycle” <http://www.avert.org/hiv-virus.htm>
4. “Zinc Finger Nuclease that Disables CCR5 Gene May Offer Potential New HIV Treatment Approach” <http://www.hivandhepatitis.com/2008icr/icaac_idsa/docs/111808_a.html>
5. “Zinc Finger Gene Therapy Produces HIV-Resistant CD4 T-cells” <http://www.aidsmap.com/page/1681138/>
6. “Phase I Dose Escalation Study of Autologous T-cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases in HIV-Infected Patients” <http://clinicaltrials.gov/ct2/show/NCT01044654>