New protein discovered for HIV therapy

AIDS Research: Scientists discover potent protein for HIV therapy

12/24/2010

Researchers at the Hannover Medical School (MHH) have developed a new treatment approach for HIV therapy. While previous drugs were able to prevent the multiplication of HI viruses only by engaging in human cells, the researchers at MHH use a newly discovered protein to directly attack the viruses. The new method promises fewer side effects and could be used against other viral diseases such as Ebola or hepatitis, said the scientists of the MHH. The development of a corresponding drug, however, is expected at the earliest in six to seven years.

The research team led by Reinhold Schmidt and Wolf-Georg Forssmann of the MHH has developed a new approach to the treatment of HIV together with scientists from the University of Ulm and this in the current issue of the journal „Science Translational Medicine“released. According to the results of their clinical study, the peptide they discovered, VIR-576, can be used effectively to inhibit the proliferation of HI viruses in patients, the researchers said. The treatment did not start at the cell nucleus of the body's own cells of HIV patients, as it did in the past, but directly against the virus itself, emphasized the MHH experts.

HI viruses must fuse with the body's own cells
In order to multiply in the body of the HIV-infected and infect via the bloodstream more cells, the HI virus must merge with the human cells. This is where all previous treatment methods come in and try to suppress the multiplication of the virus in the body's own cells or to modify the surface structure of the cells so that the HI viruses have no possibility to dock. However, as it always intervenes in the cells of HIV patients, threatening significant side effects. This could change with the use of the peptide VIR-576, so the hope of MHH scientists. Because the peptide does not interfere with the human cells, but blocks the so-called fusion protein, a protein which is necessary for docking to the surface of the human cell, directly in the envelope of HI viruses. „Without this protein, the viruses can not invade human cells“, emphasized Wolf-Georg Forssmann, head of the research group Experimental and Clinical Peptide Research at the MHH. Thus, the number of viruses in the blood of HIV-infected people with the new method can be efficiently reduced and avoid an outbreak of the immune deficiency disease, without similar side effects occur as in the previous treatment methods, the researchers said.

New active substance without comparable side effects
The „Side effects of the previously used drugs are all based on the fact that they always attack the nucleus of the human cell“, explained the director of the Department of Immunology and Rheumatology at the MHH, Prof. Reinhold Schmidt. As a result, for example, symptoms such as disorders of blood formation, kidney or liver problems occur, said the expert. The use of the peptide VIR-576 to block the fusion protein on the envelope of HI viruses such side effects are not to be expected because VIR-576 does not penetrate into the human cells, so the researchers of MHH on. According to their expectations, the previous clinical studies have shown no serious side effects of VIR-576, write Schmidt and colleagues in the journal „Science Translational Medicine“. In their study, the researchers administered 18 high-dose infusions of the VIR-576 peptide to 18 HIV-infected individuals for ten days, reducing the number of active viruses in the blood of patients by up to 91 percent. In the worst case, slight side effects such as rash, headache or diarrhea have occurred, the researchers report.

Fewer resistances to be feared
„This is a completely new mode of action against viruses“ emphasized Reinhold Ernst Schmidt and explained that with the help of the peptide patients can also be treated, in which the conventional HIV drugs are no longer effective. Because the HI viruses quickly develop resistance to the common preparations because they repeatedly change their properties in the course of their rapid multiplication. So far, patients are always treated with a combination of three drugs to minimize the risk of resistance as low as possible, the researchers said the MHH. „If you only gave one, resistance would develop within weeks“, so Schmidt. According to the researchers, however, the newly discovered peptide VIR-576 has a very low probability of resistance since VIR-576 targets a part of the virus that is difficult to mutate without at the same time losing its function. „Due to the new mechanism of action, VIR-576 is also effective against HIV viruses that have already become resistant to other drugs“, said Frank Kirchhoff of the University of Ulm, who also participated in the clinical study.

Development planned as a tablet form
Even if the new treatment approach seems to be promising, the previous administration of the drug as a continuous infusion in everyday medical practice is not practical. But another dosage form has yet to be developed, because VIR-576 decays too quickly in the current methods or is degraded by the body. Frank Kirchhoff emphasized that „the substance is not yet suitable for widespread clinical use“ is. Because not only the continuous infusion is a problem, also the production of the peptide is so far too expensive and expensive, said Kirchhoff. Therefore, the researchers of the MHH work according to their own information at high pressure to develop from the peptide as soon as possible a more suitable drug. „We try to make VIR-576 a small molecule so that it can be used without problems in therapy“, explained Reinhold Schmidt. One of the goals is to bring the drug in tablet form on the market. „We now know the molecule and its binding site on the HI virus. For the future, we plan to chemically manufacture the molecule so that it fits into a tablet“, so Schmidt. However, with all the tests and advancements that MHH professionals are still facing, the introduction of a VIR-576-based drug will take another six to seven years.

Treatment approach could also help with other viral diseases
With their new approach to VIR-576 treatment, MHH researchers hope to be able to successfully combat other viral diseases such as influenza, mumps, measles, hepatitis B and hepatitis C or Ebola in the future, as the viruses must also fuse with the body's own cells to multiply. "So the mechanism we have developed could be very relevant to many other viruses"; emphasized Reinhold Schmidt. Also the Hamburg HIV expert Prof. Andreas Plettenberg, director of the ifi Institute for Interdisciplinary Medicine on the grounds of the Asklepios-Klinik St. Georg, was cautiously optimistic considering the current study results: „That's certainly an interesting and innovative approach. Whether the hope for fewer side effects and less resistance is true, but still has to show. This will only become apparent in further studies with many patients and long observation times“, stressed the expert. Plettenberg added: „There are still many hurdles to be overcome, but the first steps have been taken. And one can only hope that the further steps are successful“.

Already today, the proliferation of HI viruses in the host cells of those affected with conventional preparations can be relatively well inhibited, so that in countries such as Germany HIV-infected with consistent therapy an almost normal life expectancy, even if they have to stay in treatment for a lifetime , Problematic are the occurring resistances and the sometimes massive side effects of HIV medication. Here VIR-576 could represent a real alternative in further development.

Peptide VIR-576 derived from natural transport protein
In 2007, the MHH researchers discovered the peptide VIR-576 in the study of the virus-inhibiting function of proteins that normally occur in human blood. They came across a natural transport protein in the body, the so-called alpha-1-antitrypsin and developed from this the more potent VIR-576. „We first isolated the protein from the blood and then dissolved the peptide from the total protein“, explained Reinhold Schmidt. More than 600 different synthetically produced peptides were derived from the one transport protein at the MHH, whereby in each case small changes for blocking the fusion protein were tested on the envelopes of the HI viruses. According to the MHH researchers, the development of their innovative treatment method was successful with VIR-576. (Fp)

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Picture: Gerd Altmann