Three Novel Approaches to Treating HIV
Much progress has been made in AIDS treatment research, resulting in more than twenty anti-HIV drugs now available, with new combinations and easier to use formulations coming to market. Potent anti-HIV therapy has posed an ever growing list of questions about how best to use the therapies and how to manage side effects. Increasingly the concerns of availability and use of the current drugs in developing nations captures growing attention as well. In the midst of the all this, however, it's important not to lose site of the need for wholly innovative approaches to treating HIV -- whether that be with the currently approved drugs or with entirely new types of therapies. This article highlights three such approaches. The first is an attempt to flush the reservoir of HIV in resting cells. The second forces drug resistance as a strategy for late-stage treatment. The third combines multiple targets for gene therapy.
Flushing the Reservoir
Despite current potent anti-HIV regimens' ability to reduce plasma HIV levels to undetectable levels for prolonged periods, they do not result in eradicating HIV from the body or a cure for AIDS. It's believed that currently available anti-HIV drugs don't wholly eliminate HIV from the body because the drugs primarily act on actively reproducing virus. In addition to virus that is actively replicating, HIV can also infect a cell and the cell can go dormant or quiet. As long as the cell is quiet, the HIV inside it is also quiet -- and undetectable from both the immune system and the effects of anti-HIV drugs. If or when that cell becomes active, the HIV inside of it becomes active and can rekindle HIV infection in the absence of anti-HIV drugs. These quiet or resting HIV-infected cells act as a reservoir for HIV.
Some researchers believe that a cure for AIDS requires completely eliminating or eradicating HIV from the body, including destroying the reservoir of HIV-infected cells. It has been proposed that one way to do this could be to activate resting cells in the reservoir while a person is taking potent anti-HIV drugs for an extended period of time. If all of the HIV-infected cells are activated, those cells would be blocked from effectively producing virus and would be destroyed. For this to work though requires reaching every single resting infected cell, a rather high hurdle.
Several experiments have attempted this activation strategy. Some have included the immune stimulator, interleukin-2 (IL-2, Proleukin). Others combined IL-2 with a very potent immune activator called OKT3. The OKT3 side effects overwhelmed any benefits, however, and studies were stopped. More recently, late in 2005, an article appeared in the medical journal The Lancet reporting encouraging results with the use of valproic acid. Project Inform reported on that study in PI Perspective #40.
There are different mechanisms by which HIV remains quiet/latent. Dean Hamer of the National Cancer Institute proposes that it may be possible to flush more of the reservoir by using activation strategies that activate through different mechanisms, called CIS and TRANS. Valproic acid works through CIS activation. Another researcher, David Margolis, has conducted initial studies using valproic acid (see PI Perspective #40). Another class of compounds called DAG lactones work through TRANS activation. Using a combination of CIS and TRANS activators (valproic acid + a DAG lactone compound, either LMC03 or LMC07), Hamer notes excellent success in activating quiet cells, at relatively low doses, with few side effects. Hamer proposes another study of CIS and TRANS activation approaches (valproic acid with a DAG lactone compound) along with an immunotoxin (to target and destroy activated cells) in combination with potent anti-HIV therapy. This is the type of research that may bring the field several steps forward.
Recently the American Foundation for AIDS Research (amfAR) hosted a roundtable on HIV eradication/activation that led to a new amfAR funding mechanism for this type of research. More is needed to explore the potential of HIV eradication strategies. Volunteers who participate in studies are true warriors of progress in the field, but not everyone can, wants to or should participate in studies of this nature. Another way to support innovative studies is by donating to the Foundation for AIDS and Immune Research (www.foundationFAIR.org) and specifically encouraging studies attempting to eradicate the reservoir of infected cells. For more information on eradication strategies, see:
Drug Resistance Strategy
As noted in the article "Drug Pipeline Offers Diverse New Therapies and Hope," there are a variety of new entry inhibitors in development. Currently, there are three major classes of entry inhibitors including 1) CD4 inhibitors, 2) co-receptor inhibitors and 3) fusion inhibitors. Below is a grid outlining the products in development.
There have been a few interesting observations about entry inhibitor resistance -- particularly as it relates to the drug Fuzeon. The development of resistance to Fuzeon does not result in resistance to co-receptor inhibitors. In general people whose virus develops resistance to Fuzeon appear to remain fully sensitive to co-receptor inhibitors. Even more interesting is that as people develop resistance to Fuzeon, changes appear in the virus population -- forcing diverse virus to become more similar or homogenous with regard to co-receptor use.
There are two commonly discussed co-receptors, CCR5 (R5) and CXCR4 (X4). HIV that uses R5 to infect cells is generally considered less aggressive than HIV that uses X4. Most people have a mixed population of virus, with some percentage using the R5 to infect cells and other virus using the X4. A challenge for entry inhibitor research is that an R5 inhibitor has no impact on X4 using and vice versa. A fear of R5 inhibitor research is that it may give the more aggressive X4-using virus an advantage, resulting in worse outcomes. This might speak to the need to combine approaches, which would target both R5- and X4-using virus. This may ultimately be the best use of these types of entry inhibitors.
The observation that virus rebounding while a person is on Fuzeon becomes more homogenous, opens up a new possibility and potential for the co-receptor inhibitors. When someone develops resistance to Fuzeon, they may indeed be more susceptible to the beneficial effects of co-receptor inhibitors.
While the most potent effect of Fuzeon will undoubtedly always be its anti-HIV activity, it might also be that resistance to Fuzeon may have some benefit in increasing the potency and effectiveness of these other therapies. This is not the only time where the development of resistance to anti-HIV drugs has been observed to have some possible beneficial effects. Virus resistant to Epivir (lamivudine, 3TC) may be more susceptible to the anti-HIV effects of other drugs. Also, protease inhibitor resistant virus may be less fit, or less capable of causing damage to the immune system. In none of these cases is resistance considered a good thing. However, the information suggests that in some cases when resistance does develop it can be used to one's advantage rather than wholly being viewed as a loss of the use of drugs or classes of drugs. This opens the door for entirely new kinds of research, especially beneficial for people who have developed resistance to many anti-HIV drugs.
Ongoing studies of co-receptor inhibitors include people taking Fuzeon as well as folks who have developed resistance to Fuzeon. Emerging data from these studies will allow researchers to have some indication as to the benefit of using Fuzeon in combination with co-receptor inhibitors and using these inhibitors sequentially, following Fuzeon failure. Results from current studies will point the direction for future research on this strategy. For more information, see:
Gene Therapy for HIV
Research on gene therapy for HIV infection is moving from its infancy to adolescence. The PI Perspective #41 article "A Very Different Approach to HIV Treatment" refers to a Johnson & Johnson sponsored study of ribozyme-modified stem cells, which was highlighted in newspapers across the country. Other innovative gene therapy research continues. Southern California is a hub of activity in this field, with world renowned experts at the City of Hope and long-standing collaborations with the University of California, Los Angeles (UCLA), particularly the Children's Hospital.
At a recent annual symposium on HIV/AIDS in Palm Springs, City of Hope's Dr. John Rossi, a pioneer in gene therapy for HIV, presented the outline of a study which will be recruiting later this year. Like the Johnson & Johnson study mentioned previously, this study will also genetically modify stem cells. Stem cells are often called the mother of all cells, as a single stem cell can divide and differentiate into the entire spectrum of immune cells. By targeting this particular cell with anti-HIV genes, it's theoretically possible to repopulate the entire spectrum of immune cells with cells that can resist HIV infection.
Dr. Rossi's study is so innovative because it combines three anti-HIV gene therapy targets. Just like the combination of anti-HIV drugs, targeting steps in HIV's lifecycle worked better than using single drugs, Dr. Rossi's approach combines three approaches to targeting HIV -- and this will be done in addition to the use of anti-HIV drugs. The study will be the first triple-construct approach tested in humans with HIV. The hope is that by combining different approaches resistance issues will be lessened and potency will be enhanced.
The three targets are TAT/REV, TAR and CCR5. TAT/REV and TAR are HIV genes, and CCR5 is a cell factor, which will be targeted to block the virus from entering the cell. This gene therapy approach will include an approach called RNAi, which we discussed in PI Perspective #36, in the article "Interfering With RNA: Kill the Messenger."
Preliminary data show that this approach does not appear to be toxic to the cells and in test tubes they were able to protect cells from infection for a long time. They have looked at these cells in test tubes after exposure to HIV and after 42 days they are not able to detect virus. This is considered a very long time in these experimental conditions. For more information, see:
While the advent of potent anti-HIV therapy has left a legacy of critical research questions to answer, there is also a need to get beyond highly active antiretroviral therapy (HAART) -- to push HIV treatment to new frontiers, to a cure for AIDS. The three strategies highlighted above are but a few examples of this kind of research. Each represents a frontier of harnessing new information and testing to concepts and strategies. These kinds of studies promise to be the building blocks of progress. No one can predict their outcome but each, regardless of outcome, will help to shape progress in the field.
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