“The way to prevent AIDS,” said Dr. Beatrice Hahn of the University of Alabama in Birmingham at the recent 9th Retroviruses Conference in Seattle, “is to become more like chimpanzees.” She hypothesized that when chimps -- and the 16 species of African monkeys found so far to be naturally infected with SIV, the simian equivalent of HIV -- were initially infected with SIV thousands of years ago, they suffered the same dire consequences as humans now suffer from HIV. But over time their immune systems have adapted to live with their virus. “The trick is to figure out how the chimp’s [immune system] decides what to do and when,” concluded Dr. Hahn.
In his talk, Dr. Marc Feinberg of the Emory University School of Medicine in Atlanta explained that these animals harbor just as high viral loads as humans with chronic or even full-blown AIDS. But they rarely get sick, he hypothesized, because their immune responses to SIV are much less aggressive, and therefore there is much less collateral damage to the cells by the immune system itself. Indeed, he believes that chronic immune system activation may be the primary mechanism driving the depletion of CD4 T cells and not the virus itself. (However, the virus is certainly toxic, and Dr. David Ho of the New York Rockefeller University’s Aaron Diamond AIDS Research Center emphasized in his talk his belief in the primacy of the virus in destroying CD4 T cells.)
Dr. Alan Landay of the Rush-Presbyterian Medical Center in Chicago has said the “new” emphasis on immune restoration, and immune hyperactivity in particular, is really an example of another swing of the proverbial HIV treatment pendulum. He has pointed out that back in 1983 and 1984, before the introduction of HAART or even AZT, there were attempts to dampen the immune responses against HIV. But likely because the agents used then depressed too much of the immune system, they failed. Today’s means of manipulating an overactive immune response against HIV are both more targeted and more varied in their approaches, as evidenced by the following preliminary but promising studies presented at the 9th Retroviruses Conference.
At his poster presentation, Dr. Northfelt of the University of California in San Diego described a product called Cytolin that he believes stops the CD8 cytotoxic T cells (CTL’s) that kill HIV-infected CD4 cells from also killing CD4 cells that are not infected with HIV. He explained that many CTL’s contain an adhesion molecule called LFA on their surface that helps the CTL’s interact with CD4 cells by binding with a “sister” molecule (called ICAM) on the surface of CD4 cells. While those CTL’s that contain LFA will kill CD4 cells that are infected with HIV, they may also kill CD4 cells that are not infected with HIV. Cytolin is an antibody to LFA that blocks the ability of LFA to function, and hence seems to stop the initial overkill by CTL. Dr. Northfelt explained that this drug “sort of got lost for awhile” because it went into an underground system where patients were treating themselves with it without any real clinical science being done to determine whether it was safe or effective. He said that in the mid-1990s about 300 people in Los Angeles were treated with it regularly. Because of a number of anecdotal reports of dramatic improvements in health with Cytolin, a company was formed specifically to try to develop this drug as a legitimate pharmaceutical product. He presented preliminary results showing that in the first organized trial of Cytolin, where it was given along with HAART, it seemed to be well tolerated and to both decrease viral loads and increase CD4 counts above those seen on HAART only. One of its problems, however, is that the antibody is made by using mouse cell cultures, so it looks foreign to the body and if the immune system is still capable, it tries to eliminate it. Therapeutic antibodies used in cancer and rheumatoid arthritis have had this same problem, but many of them have recently been humanized. Dr. Northfelt said that ways to also humanize Cytolin will have to be found if it is to be more broadly applicable.
Another approach to dampening and/or redirecting an out-of-control or badly regulated immune response may be to “re-boot” the immune response by stimulating the innate or first line, non-specific responses. Long treated as the Cinderella of the immune system, researchers felt the innate immune system’s only job was to non-specifically hold germs at bay until the more specific cells of the adaptive response kicked in. But now scientists believe the strength or type of innate immune response also helps determine or direct the type of adaptive immune response that will take place. The results from two encouraging preliminary trials involving the stimulation of innate immune cells called dendritic cells were presented, one on end-stage disease and the other on those with CD4 counts above 500.
At her poster presentation, Dr. Judith Lisziewicz of the Research Institute for Genetic and Human Therapy in Washington, D.C. presented “very exciting and surprising” results of a DNA vaccine used on very sick rhesus macaques. These monkeys are from Asia, and unlike the African species mentioned earlier, have not been infected with SIV for thousands of years. Like humans, they have only recently contacted their virus, either when housed with African primates or more likely when injected with a form of it by researchers. Also like humans, and unlike the African monkey species, their viral load is a good measure of disease progression. Normally, they survive only 14 months or less after being infected with a potent form of SIV. But two of three monkeys in her study given a vaccine containing most of the genes for SIV are still alive after two years. (The one monkey that died had the lowest viral load and was the one most expected to survive, but died of kidney failure.)
Other DNA therapeutic vaccines, or vaccines for those already infected and that contain genes, as opposed to proteins or bits of proteins, from SIV have been tried but not in end-stage disease nor with any success. Indeed, this is the first demonstration that a therapeutic vaccine works in monkeys. The difference, surmised Dr. Lisziewicz, is that this vaccine, called DermaVir, is a topical (applied directly to the skin instead of being injected) immunization that primarily stimulates innate immune cells in the skin called langerhans cells. These cells then migrate to lymph nodes where they mature and become known as dendritic cells. As dendritic cells, their function is to present parts of the virus that they captured in the skin (whether from a vaccine or the virus itself) to helper CD4 T cells that are specific for SIV (or HIV), thus inducing them to in turn stimulate virus-specific antibodies and CTL’s.
The most remarkable finding is that DermaVir was only used in very sick, end-stage monkeys. The monkeys were so sick that Dr. Lisziewicz said they had trouble getting permission to even attempt their experiment, as their supervisors wanted to end the monkeys’ suffering by putting them to sleep. In other words, this is the first clear evidence of the ability to reconstitute an HIV-specific immune response in end-stage AIDS (assuming, as is most likely, that SIV operates in the rhesus macaque as HIV does in humans). Dr. Lisziewicz’s group is hoping to begin a human study in September, if they can find a way to reformulate the monkey vaccine into a human-adapted vaccine by then. She is also hoping the vaccine will work at earlier stages of HIV disease.
Another poster demonstrated the trial results of a product that enhances the innate defense in early HIV disease when CD4 counts are above 500 and patients are not yet on HAART. The product is called Murabutide (MB), and at an earlier conference, results were presented that showed it increases the CD4 cell count in end-stage patients who are failing HAART. But at the 9th Retroviruses Conference, Dr. X. De La Tribonniere of ISTAC Biotech in Lille, France presented a pilot study highlighting MB’s ability to also increase the CD4 count in patients naïve to HAART. Dr. De La Tribonniere described the results of MB as “like those of a vaccine.” Since MB is a synthetic version of a bacterium’s cell wall, it likely stimulates the skin langerhans cells similarly to DermaVir. This is because langerhans cells are in the skin precisely because they want to pick up bacteria; this is what they normally do. By targeting innate cells, both MB and DermaVir may, by restarting an innate immune response against HIV, allow the innate cells to redirect the adaptive response to one that isn’t “out of control.”
A fourth way to perhaps help contain an overactive immune system is through the consumption of anti-inflammatory foods and/or supplements. Unfortunately, this information was not provided at this conference, but nutritionists and literature on nutrition can be helpful. However, there was one intriguing study showing that just as too much virus or too much of an immune response can be dangerous, so too can too much of a supplement. The study showed that “for unknown reasons, vitamin A supplementation may have deleterious effects on pneumonia in some [African] children.” It concluded that since the immune markers associated with lower vitamin A levels “would all assist in anti-HIV immunity, moderately low vitamin A levels might actually be preferable to the currently defined ‘normal’ levels.”
Finally, instead of trying to dampen or otherwise regulate the immune response, some immune-based therapies aim at correcting the results of a poor immune response against HIV, i.e., a low CD4 count. So far the foremost agent used to increase CD4 cell counts has been Interlelukin-2 or IL-2, a cytokine or kind of natural hormone that causes CD4 cells to grow and divide. This conference featured numerous accounts of IL-2 trials, but the basic question of whether the improvement in CD4 cell count seen with IL-2 therapy results in a better prognosis has not yet been solved. Rather, these accounts mainly centered on safety results, showing that after more than three years of IL-2 therapy no untoward effects (other than those temporarily experienced while taking the IL-2 injections) have been seen. Two very large studies are in progress to finally answer the question as to IL-2’s usefulness, but because the studies are blinded, no results were yet forthcoming. One interesting poster presented by Dr. Jay Levy’s group at the University of California in San Francisco examined IL-2 added to HAART in the very earliest stage of HIV disease, called primary HIV infection. It found that used in this way IL-2 increases CD4 cell count and “enhances anti-HIV immune responses.” [For more complete info on IL-2 and/or to learn how to enter an IL-2 trial, see: www.aidsmeds.com/drugs/Proleukin.htm.]
The few lectures and posters on immune reconstitution at this premier scientific conference on HIV were dwarfed by the many studies there on chemotherapeutic antiretroviral strategies and their side effects. But each year more immune-based studies are appearing at this conference, lending hope that a two-pronged, virologic and immunologic approach will result in our someday being “more like chimpanzees.” This “new” emphasis on immune reconstitution should also spur our efforts to save our nearest and very endangered relatives from extinction. Dr. Hahn did mention that the chimp population today is around 150,000, down from over two-million fifty years ago.
Jo Ann Berg is a free-lance writer based in Ann Arbor, MI. She has written AIDS articles for AIDS Treatment News, amfAR’s Treatment Directory_, the GMHC newsletter, and some Michigan publications._