In early March 2019, news made headlines around the world that for the second time, an HIV patient had been completely cured of his disease, allowing him to stop taking his medication. After several decades of intensive research, the chronic infection caused by the HIV virus is now easily treatable, but scientists are already working on even more effective therapies with the aim of further improving the quality of life of HIV patients or one day even curing the disease entirely.
Attack from several sides
The human immunodeficiency virus – HIV – is quite insidious: on the one hand, it specifically attacks only the immune cells of our body, mainly T lymphocytes (T cells), but also macrophages and monocytes. The virus then lies dormant for a long time until it eventually breaks out and leads to the immunodeficiency disease AIDS (acquired immunodeficiency syndrome). On the other hand, HIV belongs to the group of retroviruses. These incorporate their own blueprint into the DNA of the infected cells. As the disease progresses, more and more cells of the body’s defenses die, leaving patients highly susceptible to other infectious agents(1) .
The drugs used to date intervene at various points in the infection process. Some, for example, prevent the virus from entering the immune cells by blocking the CCR5 receptor. CCR5 actually has the task of recognizing certain signal molecules in the blood in order to guide the immune cells to inflammation sites, for example. But HIV attaches itself to CCR5 and uses this receptor as a gateway into the cells. Other drugs act inside the cell and block molecules that are involved in the replication of the viral genome. Since the mid-1990s, several active ingredients have been combined in a single tablet to delay the development of resistance. Nevertheless, it is very important that HIV patients take their medication consistently. Even if the therapy has become much easier and more tolerable due to the combinations, it is still sometimes accompanied by considerable side effects(2) .
Eliminating viruses with antibodies
The latest trend in HIV research is so-called broadly neutralizing antibodies, or bNAbs(3) . Scientists hope to use them to solve several problems at once. In addition to increased safety, improved efficacy, and a longer-lasting treatment effect, bNAbs are also expected to combat resistance. Because as viral DNA is copied in infected cells and integrated into the genome, errors creep in. And sometimes these "copying errors" cause the proteins that make up the virus to change. As a result, antibodies designed to recognize specific protein structures of HIV were often quickly ineffective. bNAbs consist of several antibodies, each of which can recognize and bind to different areas on the viral envelope. This combination of multiple agents makes it harder for viruses to develop resistance. The antibodies, which are injected either under the skin or directly into the blood, also remain in the body longer than previous HIV agents and – according to the researchers’ working hypothesis – can be administered less frequently(4) .
Keeping HIV out
Another approach to HIV treatment is not to attack the virus directly, but to protect the immune cells from being attacked. For this purpose, the CCR5 receptor can be blocked with an antibody – the door is slammed in the face of the viruses, so to speak. In addition to CCR5, the CD4 receptor is also suitable: Via CD4, the HI virus differentiates immune cells from other cells; after binding to CD4, it penetrates the cells via CCR5(5) . First antibodies that can block these surface receptors are currently being investigated in clinical trials. Already approved in the U.S., a monoclonal antibody – ibalizumab – is used in HIV patients when their viruses have become resistant to previously available HIV drugs. This antibody prevents changes in the three-dimensional structure of HIV and/or the surface receptor CD4 after binding to the cell surface, blocking its entry into the cell.
How to make the immune system resistant
However, there are also people for whom treatment with CCR5 blockers would not be necessary: Their cells carry a mutation in the gene for the CCR5 receptor (delta32) that causes it to be produced incorrectly and no longer incorporated into the cell surface. About one in 100 people have both copies of the CCR5 gene, making them resistant to many strains of HIV(6) .
In 2007, an HIV patient was also diagnosed with leukemia, a form of cancer in which the stem cells that produce blood and immune cells multiply uncontrollably. After chemotherapy failed, the doctors treating the patient at the Charite hospital in Berlin performed a stem cell transplantation. In this treatment, all of the patient’s own stem cells are first destroyed and then replaced by those of a donor. However, the transplanted donor cells had the Delta32-CCR5 mutation and formed immune cells without this receptor. As a result, the HI viruses could no longer penetrate the immune cells, and after some time the patient was able to discontinue his antiviral medication. This case became known worldwide as the "Berlin patient"(7) . And in March 2019, another case, this time in London, made headlines.
Due to the severe side effects, however, this procedure is not suitable as a standard therapy for curing HIV. Scientists are already working on other techniques to prevent the viruses from entering the body in the long term. Gene therapies play a significant role in this; initial studies on the targeted modification of CCR5 are already in phase II. But even with gene therapies, many challenges still need to be overcome before they can be used clinically. For example, gene therapy must be able to reach all stem cells so that no more cells with CCR5 are produced that would otherwise continue to be susceptible to HIV infection. The same is true for immune cells already formed and infected, in which the virus lies dormant(8) . Care is also taken to ensure that only body cells are modified. A case like the one in Hong Kong, where a researcher equipped egg cells with an altered CCR5 receptor during artificial insemination without the permission of the authorities, should not and must not be repeated.
In order to be able to offer patients already infected with HIV improved treatment options or even the prospect of a complete cure in the future, the work of scientists at research institutes and companies is continuing. The efficacy of the therapy and the safety of the patients are always the top priority.