HIV infection can be treated today, but it is not curable. Until now, anyone who has the AIDS virus has had to take antiviral medication every day. But now researchers have developed a new active ingredient that only needs to be injected under the skin once every six months. In addition, this remedy does not apply to an enzyme of the HI virus like previous therapies, but to its capsid – the protein shell that contains the genetic makeup of the AIDS virus. This prevents the viral DNA from entering the host cell nucleus and thus inhibits virus replication. In a first clinical trial, the GS-6207 has been proven to be tolerable and long-acting.
There are over 80,000 people living with HIV in Germany, and there are more than 30 million worldwide. Contrary to the 1980s, the diagnosis of HIV is no longer a death sentence because there are now drugs that effectively inhibit the reproduction of the HIV virus in the body. Some of these therapies even work so well that the viruses are no longer detectable and HIV-infected people are therefore not contagious even with unprotected sex. But in order to achieve such an effect, those affected have to take these agents daily, usually even a whole cocktail of different active ingredients. This requires a lot of discipline and also causes side effects. In addition, effectiveness can develop over time due to the development of resistance. Scientists have therefore been looking for active substances that have a longer-lasting effect and need to be taken less frequently.
Attack on the viral capsid
John Link of Gilead Sciences and his colleagues may have found this. In the course of their work, they looked for molecular active substances that do not attach to one or more enzymes of the AIDS virus, as in previous drugs, but to its capsid. This capsule, which consists of proteins, envelops the viral genome and plays an important role in introducing viral DNA into the cell nucleus of the host cell. “The correct formation and integrity of the capsid are therefore essential for the infectivity of the virus,” the researchers explain. However, the active ingredient GS-6207 developed by them binds to the proteins of the HIV capsid and thus interferes with its function. As a result, the virus can no longer freely insert its genetic instructions into the cell nucleus. In cell culture experiments, relatively low concentrations of the agent were sufficient to deform the viral capsids and thus prevent the formation of functional HI viruses.
In further laboratory experiments, GS-6207 was found to be effective against all strains of HIV-1 tested and also against two variants of the HIV-12 subtype, which occurs primarily in West Africa. Because the active ingredient starts at a different point in the reproductive cycle of the HI virus than previous medications, it also inhibits the virus strains that are already resistant to current therapies, as Link and his team report. “When GS-6207 is combined with other antiretroviral agents, it shows synergy effects and demonstrates its suitability for combination therapies.” Such a combination of substances with different mechanisms of action and starting points is considered the most effective way to suppress the development of resistant virus variants for as long as possible.
Potentially effective for up to six months
To test the suitability of the new agent for therapy in humans, Link and his colleagues have already carried out a first phase 1 clinical study. It is used to test the tolerance and the activity profile of a drug in the different tissues of the body. For this, 32 healthy volunteers received a single injection of GS-6207 under the skin, eight others received a placebo. As the researchers report, the drug proved to be well tolerated; only a few subjects experienced temporary pain and reddening of the skin at the injection site. The results on the activity profile were also positive: at a dose of 100 milligrams or more, the agent remained detectable in the body for at least twelve weeks in a concentration sufficient to inhibit viruses. At 300 milligrams, the effective range was over 24 weeks. This confirms that GS-6207 degrades slowly and can therefore have a long-lasting effect.
Link and his team have already tested whether and how well GS-6207 can inhibit the multiplication of HI viruses in humans in a supplementary pilot study. 24 participants with an untreated HIV infection were injected with different doses of the drug. Nine days after the injection, the viral load of these subjects had already dropped measurably, as the researchers report. In their view, these results confirm that GS-6207 is suitable for long-term therapy against the HI virus – and as a good addition to existing medications. “Because GS-6207 only needs to be administered subcutaneously at large intervals, it would also be an attractive candidate for simple HIV prevention in high-risk populations,” said Link and his colleagues. Until then, however, further clinical studies must now examine the suitable dose and the effect of the agent.
Quelle: John Link (Gilead Sciences, Foster City) et al., Nature, doi: 10.1038 / s41586-020-2443-1
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