New protein discovered for HIV therapy

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AIDS research: Scientists discover effective protein for HIV therapy

Researchers at the Hannover Medical School (MHH) have developed a new treatment approach for HIV therapy. While previous drugs could only prevent the reproduction of the HI virus by interfering with human cells, the MHH researchers managed to attack the virus directly with the help of a newly discovered protein. The new method promises fewer side effects and could also be used against other viral diseases such as Ebola or hepatitis, the MHH scientists explained. However, the development of a corresponding drug can be expected in six to seven years at the earliest.

The research team led by Reinhold Schmidt and Wolf-Georg Forssmann from the MHH, together with scientists from the University of Ulm, developed a new approach to the treatment of HIV and published it in the current issue of the scientific journal "Science Translational Medicine". According to the results of their clinical study, the peptide VIR-576 they discovered can be used effectively to inhibit the multiplication of HI viruses in patients, the scientists explained. The MHH experts emphasized that the treatment did not start with the nucleus of the body's own cells in HIV patients, as was the case with previous methods, but directly with the virus itself.

HI viruses must fuse with the body's own cells. In order to multiply in the body of HIV-infected people and to infect other cells via the bloodstream, the HI viruses must fuse with the human cells. This is where all previous treatment methods come into play and try to suppress the multiplication of the virus in the body's own cells or to change the surface structure of the cells in such a way that the HI viruses no longer have any possibility of docking. However, since there is always intervention in the cells of HIV patients, there are significant side effects. This could change with the use of the peptide VIR-576, so the MHH scientists hope. Because the peptide does not interfere with human cells, but blocks the so-called fusion protein directly in the envelope of the HI viruses, a protein which is necessary for docking to the surface of the human cell. "Without this protein, the viruses cannot penetrate human cells," emphasized Wolf-Georg Forssmann, head of the experimental group and clinical peptide research at the MHH. With the new method, the number of viruses in the blood of HIV-infected people can be efficiently reduced and an outbreak of the immune deficiency disease avoided without the side effects similar to those of previous treatment methods, the researchers further explained.

New active ingredient without comparable side effects
The "side effects of the medications used so far are all based on the fact that they always attack the nucleus of the human cell," explained the director of the Clinic for Immunology and Rheumatology at the MHH, Prof. Reinhold Schmidt. For example, symptoms such as problems with blood formation, kidney or liver problems can occur, the specialist emphasized. Such side effects cannot be expected from the use of the peptide VIR-576 to block the fusion protein on the envelope of the HI viruses, because VIR-576 does not penetrate the human cells, the MHH researchers continued. According to their expectations, the previous clinical studies had not shown any serious side effects of VIR-576, Schmidt and colleagues write in the journal "Science Translational Medicine". As part of their study, the researchers had given 18 HIV-infected people a high-dose infusion of the peptide VIR-576 for ten days, thereby reducing the number of active viruses in the patient's blood by up to 91 percent. In the worst case, slight side effects such as rash, headache or diarrhea have occurred, the researchers report.

Fear of less resistance "This is a completely new mode of action against viruses" emphasized Reinhold Ernst Schmidt and explained that the peptide can also be used to treat patients for whom conventional HIV medication is no longer effective. Because the HI viruses quickly develop resistance to the common preparations because they change their properties again and again in the course of their rapid multiplication. So far, patients have always been treated with a combination of three drugs to keep the risk of resistance as low as possible, the MHH researchers explained. "If you only gave one, resistance would develop within weeks," says Schmidt. According to the researchers, the likelihood of resistance to the newly discovered peptide VIR-576 is very low, since VIR-576 targets a part of the virus that is difficult to mutate without losing its function. "Due to the new mechanism of action, VIR-576 is also effective against HI viruses that have already become resistant to other drugs," said Frank Kirchhoff from Ulm University, who was also involved in the clinical study.

Development in tablet form planned Even if the new treatment approach seems promising, the previous administration of the active ingredient as a continuous infusion in everyday medical practice is not practical. However, another dosage form has yet to be developed because VIR-576 disintegrates too quickly or is broken down by the body in the usual methods. Frank Kirchhoff also emphasized that "the substance is not yet suitable for wide clinical use". Because not only continuous infusion is a problem, the production of the peptide has so far been too complex and expensive, explained Kirchhoff. For this reason, the researchers at MHH are working flat out to develop a more usable drug from the peptide as quickly as possible. "We are trying to make VIR-576 a small molecule so that it can be used in therapy without any problems," said Reinhold Schmidt. One of the goals is to bring the active ingredient to the market in tablet form. “We now know the molecule and its binding site on the HI virus. In the future, we plan to chemically manufacture the molecule so that it fits into a tablet, ”says Schmidt. However, with all the tests and further developments that the MHH experts still have in front of them, the introduction of a drug based on VIR-576 will take at least six to seven years.

Treatment approach could also help with other viral diseases With their new VIR-576 treatment approach, the researchers at the MHH hope to be able to successfully combat other viral diseases such as flu, mumps, measles, hepatitis B and hepatitis C or Ebola in the future, since the viruses also use the the body's own cells have to fuse to multiply. "The mechanism we developed could therefore be very relevant for many other viruses"; Reinhold Schmidt emphasized. The Hamburg HIV expert Prof. Andreas Plettenberg, head of the ifi Institute for Interdisciplinary Medicine on the grounds of the Asklepios Clinic St. Georg, was also cautiously optimistic in view of the current study results: “This is certainly an interesting and innovative approach. However, it remains to be seen whether the hope of fewer side effects and fewer resistances will come true. This will only become clear in further studies with many patients and long observation times, ”emphasized the specialist. Plettenberg added: “There are still many obstacles to be overcome, but the first steps have been taken. And one can only hope that the next steps will also be successful ”.

The proliferation of the HI viruses in the host cells of those affected can already be inhibited relatively well with conventional preparations, so that in countries like Germany HIV-infected people with consistent therapy have an almost normal life expectancy, even if they have to remain in treatment for a lifetime . Resistance and the sometimes massive side effects of HIV drugs are problematic. Here VIR-576 could represent a real alternative for further development.

PIR VIR-576 derived from natural transport protein The MHH researchers had already discovered peptide VIR-576 in 2007 when studying 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 the more potent VIR-576 from it. "We first isolated the protein from the blood and then removed the peptide from the total protein," explained Reinhold Schmidt. At the MHH, over 600 different synthetically produced peptides were derived from the one transport protein, with small changes to block the fusion protein on the envelopes of the HI viruses being tested in each case. The VIR-576 then worked, according to the MHH researchers, regarding the development of their innovative treatment method. (fp)

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