December 5, 2011
Research aimed toward curing HIV infection by ridding the body of the virus or teaching the immune system to keep the virus under control without the need for antiretroviral (ARV) drugs -- what some refer to as a "functional cure" -- is beginning to bear fruit. Though still in the early stages, some promising treatments and technologies are now starting to be tested in humans.
In some types of clinical research (where a drug or device is tested in people), scientists know a great deal about the disease and how they want to intervene, and there is a lot of experience about how to use a particular drug or device. In HIV, we know a lot about the individual steps that the virus takes to enter and infect CD4 cells, and we know a lot about the ARV drugs designed to target those steps and shut down viral reproduction. This makes the process for testing new ARV drugs fairly straightforward.
On the other hand, there is still much we don't know about where and how HIV is able to hide out quietly in the body, which is known as latency. The consequence of these "reservoirs" of latently infected resting cells is that even when ARV drugs shut down HIV reproduction almost completely, this hidden virus can quickly bring the infection raging back to life if ARVs are stopped.
Researchers are testing new drugs that will get the virus out of hiding so that ARV drugs can treat it. Others are trying to manipulate CD4 or stem cells so that they do not get infected with HIV. Because we do not know how safe or effective these approaches are, there may be unknown risks for the people who volunteer to take them within a clinical trial.
This means that when a person enters one of these trials they should know that their participation will likely help others by advancing science but may or may not benefit them individually in the immediate term. Following are summaries of the specific interventions being considered, both the potential benefits and the potential risks to a person's health. If we can understand better how people with HIV view this kind of research, and how willing they are to enter studies of these new therapies, it will help scientists and regulators understand how to proceed with those studies.
Latent, or "hidden," infection occurs when HIV's genes (RNA) gets incorporated into the DNA of a cell. Because many immune system cells remain inactive in the body, they may never get "turned on," which is necessary for the virus to complete its cycle (e.g. the production of new viruses). The virus essentially goes to sleep at this middle stage, making the infected cell invisible to the immune system. A variety of approaches are being studied to awaken the latent HIV so that the cell can be destroyed and any virus that is produced treated using standard antiretroviral medications. The leading strategy involves the use of drugs called histone deacetylase (HDAC) inhibitors, which essentially work by stopping genes (including HIV's genes) from shutting down. While it may be possible for HDAC inhibitors to activate HIV and get it out of hiding, there is also a risk of activating other genes that could cause harmful effects in the body, such as certain types of cancer.
Vaccines are usually given preventively: Given to people before they are exposed or infected with a disease. Since the 1980s researchers have also been investigating whether vaccines can boost immune responses to the virus in people already infected with HIV. The results to date have not identified major risks, but have also not demonstrated significant benefits. Only recently have studies been initiated to look at the impact of therapeutic vaccination on HIV reservoirs, but this will become increasingly common in cure-related research. One potential (though rare) risk of therapeutic vaccination would be causing virus levels to go up, rather than down, and worsening cellular inflammation, which has been tied to things such as heart disease and kidney disease.
One of the experimental approaches that has been in the news recently involves extracting CD4 T cells from an HIV-positive individual, modifying them in the laboratory to try and make them resistant to HIV, then re-infusing them back into the same person in greater numbers. Previous studies of this type weren't very successful, because scientists couldn't get enough new cells back into the body and because the cells that were re-infused didn't live very long. Currently, a new method is drawing attention, because early results suggest it may able to modify greater numbers of CD4 T cells. This approach, involving gene modification, stops CD4 cells from producing functional receptors on their surface -- receptors called CCR5 that HIV requires to infect cells. This is done by using the zinc finger nucleases to alter the cell's genes. In the experiments so far, these modified cells proved to be resistant to HIV infection and very long-lived.
These types of cell infusion approaches can be difficult for both the patients and the scientists, as they involve being hooked up to a machine for several hours in a process called apheresis, which removes CD4 T cells from the blood. When the modified cells are put back into the body it can cause temporary side effects including chills, fever, headache, sweats, dizziness, fatigue and a body odor resembling garlic (likely resulting from the substance used to preserve the cells during modification). There are also some potential theoretical risks, which could include cancer and other health problems, if the zinc finger nucleases disrupt the wrong genes.
New studies of gene modification approaches are also considering using a brief period of immune-suppressive treatment in order to temporarily reduce CD4 T cell levels and thus "make room" for the new gene-modified cells. There is evidence that this approach will lead to greater uptake and expansion of the gene-modified CD4 T cells, but it will likely also add some risk as immune suppression can leave people vulnerable to serious infections.
The much-publicized case of Timothy Brown -- an individual who appears to have been cured of HIV infection through a complex and toxic series of treatments for leukemia -- involved the use of two stem cell transplants from a donor who lacked a functional CCR5 receptor gene (due to a rare genetic mutation). This has prompted interest in trying to use the zinc finger nuclease treatment (or other similar strategies) to modify stem cells rather than just CD4 T cells. Stem cells are "the mother of all cells," so deleting CCR5 from these cells might result in a whole new population of "daughter" and "granddaughter" cells that are resistant to infection. With this approach, a donor would not be needed, since the patient's own modified stem cells are used.
Stem cell therapies, such as those using zinc finger nucleases to modify the genes of the stem cells, can sometimes alter the wrong genes, which in rare cases can lead to serious illness. Stem cell therapy also requires the partial or full destruction of a person's existing immune system to allow the modified cells to thrive and reproduce. The risks and discomforts here can be substantial, including death from serious infections. Currently it is thought that the risks associated with stem cell transplants will limit studies to HIV-positive individuals who require them as part of treatment for cancers, but researchers are working to design methods of stem cell modification that can be eventually applied to healthy HIV-positive people.
Perhaps the most controversial aspect of cure-related research is the need to have people stop taking ARVs (described as analytical treatment interruptions or ATIs) to measure whether the procedure or drug being studied can slow or stop HIV from reproducing. Over the last several years we've learned that when people stop taking their ARVs for more than a couple of months it can lead to bursts of cellular inflammation, which in turn can cause serious illnesses. In a very large study called the SMART trial, which compared periodic ARV treatment interruptions to continuous ARV use, the inflammation that accompanied ARV interruptions was associated with a significantly increased risk of illness and death. However, interruptions in SMART were generally lengthy.
The evidence suggests that the risks may not apply to shorter-term ATIs. The FDA is currently willing to allow trials involving ATIs but the typical limit is 12 weeks. Evidence also suggests that there are other factors that should be taken into consideration when evaluating the potential risks of ATIs, such as an individual's cardiovascular, liver and kidney disease risk profile and their lowest CD4 count in the past (called the CD4 nadir). Anyone considering participating in a trial involving ATIs should review the latest information on the risks of ARV interruption with their primary care doctor.