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October / November 2010
From Mice Into Men
by Regan Hofmann with Tim Horn
THE CURE HUNTERS
A look at some of today’s hottest AIDS cure research teams
It would take more pages than are housed in this magazine to even begin to highlight all the innovative work being done around the world that could directly, or indirectly, help us find the cure for HIV/AIDS. But in order to give you a sense of the different types of approaches to AIDS cure research, we highlight a handful of teams hard at work trying to find the cure. Many of these people have yet to make big headlines because their research is still in its infancy. But they’re undoubtedly leaders in an ever-expanding pack of scientists dedicated to ending AIDS.
There are currently two basic camps of HIV cure research: cell-based (or genetic) therapies and reservoir-based therapies (to address the issue of HIV hiding out in reservoirs in the body).
But there is also the possibility of a “therapeutic vaccine”—a vaccine for people with HIV that would serve as a functional cure and achieve the same end as other functional cure approaches: no meds, HIV in check.
That’s the general overview. Now, on to the specifics.
CCR5 gene modification is a key area of AIDS cure research that is ripe with potential. Working in tandem with Sangamo BioSciences, a research team headed by Paula Cannon, PhD, at the University of Southern California is using zinc-finger nucleases (ZFNs)—synthetic DNA-binding proteins—to disrupt the gene in stem cells responsible for studding CD4 cells with CCR5. The procedure worked well in mice that were specially bred to be born without immune systems so that they could receive transplants with ZFN-modified stem cells and then be exposed to HIV. (Think: mini Berlin patients, with fur.) Cannon, working with Sangamo and John Zaia, MD, (whose other work is featured below), now hopes to conduct a similar experiment in HIV-positive patients with lymphoma who undergo chemotherapy.
Carl June, MD, and his group are working at the University of Pennsylvania on their own Sangamo-supported study exploring what happens when CD4 cells are extracted from HIV-positive people, infected with a common cold virus containing ZFNs, and infused back into the patient. While this approach is less ambitious than Cannon’s stem cell method, results involving one patient have been encouraging—his viral load was slow to rebound during a treatment interruption after receiving the ZFN-modified, CCR5-depleted CD4s. June is also developing a gene-modifying technique using technology from England-based Adaptimmune, to enhance the receptors of killer CD8 cells to seek out and destroy all cells in the body infected with HIV.
Zaia, at the City of Hope Comprehensive Cancer Center in Duarte, California, has his irons in many possibly curative fires. In addition to his group’s work with Sangamo and Cannon, they’ve also completed a preliminary study transplanting HIV-positive lymphoma patients with stem cells collected from their immune systems and modified to include genetic material—ribozymes and “small interfering” RNA (siRNA)—that block HIV from infecting new cells. Though the results were encouraging, additional studies are necessary to determine if this approach has true potential.
Several biotech companies and academic centers are trying to develop the aforementioned therapeutic vaccines, designed to enhance and broaden the immune response to HIV in people already infected with the virus.
Julianna Lisziewicz, PhD, at Genetic Immunity in McLean, Virginia, for example, is developing DermaVir, which transports synthetic viral DNA to dendritic cells through the skin. In fact, dendritic cells are the focus of several vaccine developers. There's also a vaccine from Argos Therapeutics that uses a patient’s HIV to tailor the immune response.
Thus far, results from therapeutic vaccine studies have been mixed—though they perk up the immune system and several have been shown in Phase II studies to reduce viral load, they haven’t yet exerted substantial HIV control over long periods of time without treatment.
Another ambitious goal is to force latent HIV out of its hiding places in the body.
Soon after reservoirs of sleeping HIV-infected CD4 cells were discovered, researchers set out to wake them with powerful immune-based therapies. While this helps purge HIV and render it susceptible to ARVs (a good thing), the process also causes people’s immune systems to go haywire, with potentially serious consequences (a bad thing).
David Margolis, MD, and his colleagues at the University of North Carolina at Chapel Hill have been taking a kinder, gentler approach to lure out HIV and squash it. His group is experimenting with FDA-approved drugs that block histone deacetylases (HDACs)—a group of enzymes that keep HIV quiet in resting cells. Initial experiments using the HDAC inhibitor Depakote (valproic acid)—a med that treats epilepsy—were encouraging. Margolis and his team are now seeking funds to conduct a 20-person study of Zolinza (vorinostat), an approved chemotherapy for a type of lymphoma.
Targeting HDAC, however, is just the beginning. A number of proteins and pathways believed to be responsible for HIV latency are also in scientists’ crosshairs. One such example is the ominous-sounding “programmed death-1” (PD-1), a protein found in high numbers on cells harboring HIV. By blocking PD-1 or the way it interacts with a molecule called PD-L1, it may be possible to purge the virus within. Fortunately, such compounds are in development for other diseases; unfortunately, very little is known about their potential regarding HIV.
The process of screening an infinite number of drugs and natural compounds that can coax HIV out of latency can be expensive and time-consuming. Which is why the work of Robert Siliciano, MD, PhD, and his team at Johns Hopkins University at Baltimore is important. They have developed a lab protocol that can rapidly determine whether a chemical agent can get at HIV in resting CD4 cells, a process that can potentially shorten the development time of curative interventions by 10 or more years.
Merck Research Laboratories, under the direction of Daria Hazuda, PhD, is also checking its collection of compounds using streamlined testing procedures.
Another potential problem with HIV infection isn’t that the immune system doesn’t work hard enough to clear the virus, but that it’s working too hard. According to Joseph McCune, MD, at the University of California at San Francisco, an overabundance of immune system activation to HIV simply ends up creating new targets for the virus to attack, causing HIV to overstay its welcome.
McCune and his team are studying an enzyme called indoleamine-2, 3-dioxygenase (IDO) to determine if it plays a role in this vicious cycle. If so, the results may point to a new therapeutic strategy that could both decrease levels of immune activation—itself associated with some of the diseases commonly seen in HIV infection—and lower the amount of virus that persists, bringing us closer to a cure.
The possibility of “functionally” curing HIV—in which the virus is present in the body but kept at undetectable or nearly undetectable levels—is real. About 1 in 300 people living with HIV are “elite controllers” and don’t require antiretroviral (ARV) therapy to keep their HIV undetectable, many of whom are enrolled in the International HIV Controllers Study, run by Bruce Walker, MD, at Harvard Medical School.
The goal of HIV treatment research—and, indeed, HIV eradication research—is to develop therapies that enable all people living with HIV to control their virus without the need for ongoing ARV therapy. A critical step, however, is to understand what it is about elite controllers and other long-term nonprogressors that renders them nearly impervious to the effects of HIV. Walker and his team are searching for that answer.
And, finally, it has been found that drugs that stimulate the immune system to either eradicate or functionally cure HIV infection may only stand a chance if HIV replication is stopped dead in its tracks. Therefore, before these agents are tried, it may first be necessary to intensify already potent HIV drug regimens with the use of additional tried-and-true agents.
Brigitte Autran, PhD, is hard at work with her colleagues in Paris on two studies known as “ERAMUNE” designed to show a possible benefit of intensifying therapy with Isentress (raltegravir) and/or Selzentry (maraviroc). In ERAMUNE 01, patients will receive intensified ARV therapy plus Merck’s recombinant Ad5-based vaccine. In ERAMUNE 02, patients will receive treatment intensification plus Cytheris’s immune-boosted interleukin-7 (IL-7). Both trials began in July.
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Search: cure, research, AIDS, advocacy, antiretrovirals, ARV, UNAIDS, Ryan White CARE Act, ADAP, amfAR, IAC, Kevin Frost, AIDS Policy Project, Kate Krauss, Paula Cannon, protease, vaccine, NIH, PrEP, leukemia, CCR5, Berlin, Martin Delaney, Anthony Fauci, Sean Strub, Francoise Barre-Sinoussi, zinc-finger nucleases, ZFN, CD4, RNA, CD-1, DermaVir, Merck, cell-based, genetic therapies, Sangamo BioSciences, Paula Cannon, CD8 cells, Genetic Immunity, HDAC, ERAMUNE
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