HIV becomes completely curable

HIV infection: healing becomes a concrete goal

At the 19th World AIDS Conference in Washington, international scientists presented strategies to control and ultimately eliminate latent virus reservoirs in the body of HIV-infected people.

What had already been suggested in the specialist literature and at smaller congresses, now also found political support at the 19th World AIDS Conference in Washington: the healing of HIV infection. For decades, considered almost impossible, during the five-day major event scientists and opinion leaders never tired of asserting that a new chapter in AIDS research had opened.

"None of us believe that curing HIV infection will be easy, but now is the right time to try hard," said Prof. Steven G. Deeks of the University of California in San Francisco. Because especially in the last few years there has been an enormous increase in knowledge about the interactions of the HI virus with its host organism. Thanks to new therapies, it is now realistic to one day completely remove the virus from the body of an infected person, added the Nobel Prize winner in medicine and HIV discoverer Prof. Dr. rer. nat. Françoise Barré-Sinoussi from the Pasteur Institute, Paris, added.

Global Strategic Program for the Path to Healing

What makes the researchers so certain in their assessment today after, for example, in the last 30 years - despite multiple predictions - it has not been possible to develop a preventive vaccine? And why is an international consortium starting a global strategy program under the motto “Towards an HIV Cure” right now?

"The fact that research into the HIV cure was featured so prominently in the congress program is proof of how rapidly the field has developed in recent years, so that we can now actually speak of potential scientific solutions," said Prof. Diane Havlir of the University of California at San Francisco as co-president of the conference.

For the scientists, the model for striving to make a cure possible is the case of the American Timothy Ray Brown, better known as the “Berlin patient”. Not only was he infected with HIV, but later developed acute leukemia. The internist Dr. med. Gero Hütter succeeded in 2007 at the Charité in Berlin in using a special stem cell treatment to rid Brown of both the infectious and cancerous diseases. The highlight: The stem cells came from a donor whose CD4+Due to a natural but rare mutation (CCR5-delta-32), T cells do not have any functional CCR5 coreceptors on their surface and are therefore resistant to the penetration of the HI virus. Brown has since been considered cured. "He's fine, hasn't taken HIV medication for years," said Deeks.

“The last generation fought successfully for the treatment of HIV infection, our generation now has to fight for the cure.” Michel Sidibé, Director of UNAIDS. Photo: picture alliance / dieKLEINERT.de

However, the researchers do not agree on whether the mutation alone led to this positive outcome or whether radiation, intensive chemotherapy and a massive rejection reaction (graft-versus-host reaction) also made a decisive contribution to the healing process.

When asked about recent reports that traces of HIV had been detected in Brown's blood samples, Deeks reacted calmly. Even after a successful stem cell transplant, cells from the old immune system may still be present. Nevertheless, the HIV infection does not flare up again because the majority of the new immune cells are no longer accessible to the virus.

The “Berlin patient” is still an isolated case. However, it is considered a “proof of concept” that a cure is basically possible - whereby the researchers specify the term: they differentiate between “sterile cure” with complete eradication of the HI virus from the body and “functional cure” in which the host organism immunologically controls the HIV infection without medication, analogous to the herpes virus infection, in which low amounts of virus persist for life.

Some patients already succeed in functional healing. These “elite controllers” have had normal CD4 for many years+- Cell counts and a viral load that is below the detection limit without therapy (<50 copies / ml plasma). Very small amounts of virus can only be detected in the lymph nodes using ultra-sensitive methods.

Synergies between the immune system and drugs triggered

Françoise Barré-Sinoussi, the upcoming president of the International Aids Society, reported that the elite controller status is linked to the genetic constellation of those affected, which mediates a robust cell-mediated immune response and / or the infection of CD4+- Lymphocytes and macrophages prevented.

In France there is also a small group of patients (“Visconti cohort”) who received antiretroviral therapy immediately after HIV infection. Years later, patients were able to stop taking the medication without the HIV infection returning. It is assumed that the viruses were not able to infect very many host cells due to the early antiretroviral therapy. And the few that HIV was able to penetrate perished under the long-term medication due to their normal life cycle (44 months on average).

The complete eradication of the
AIDS pathogens from the body pose great challenges for the researchers. A major reason are the latently HIV-infected cells in various compartments of the host organism, which represent a lifelong reservoir for potential virus replication. Despite years of successful antiretroviral medication (viral load below the detection limit), viral transcription can still be detected in lymph nodes, gastrointestinal tract, genital tract, spleen and bone marrow.

According to Prof. Warner C. Greene, director of the Institute of Virology and Immunology at the Gladstone Institute in San Francisco, the persistence of HIV is based on the following factors: There is a reservoir of long-lived CD4+-TCM cells (Central Memory Cells) that have integrated transcriptionally inactive HIV genome. When these memory cells divide in order to compensate for natural losses (homeostatic proliferation), the integrated HIV genome is also passed on to the daughter cells, so that the total number of latently HIV-infected cells only decreases very slowly.

In addition, virus replication - triggered by environmental stimuli - is constantly maintained at a low level (low level viral replication). Ultimately, HIV prevents the host organism in various ways from building an effective immune response. For example, immune cells need to be mobile and make contact with one another in order to be able to fight off pathogens. The Nef protein in HIV is a factor that inhibits the mobility of immune cells, as a working group at Heidelberg University Hospital recently demonstrated in animal models.

Different therapeutic options in eleven pilot studies

Currently, eleven pilot studies are pursuing the goal of healing with different approaches. These include: gene therapy, therapeutic vaccination (to strengthen the immune system), intensification of existing therapy and attempts to activate HIV-infected reservoir cells and then to eliminate them.

Following the example of the “Berlin patient”, attempts have been made to artificially induce the CCR5-delta-32 mutation using genetic engineering methods. Six HIV-positive men on antiretroviral therapy (undetectable viral load and CD4+Cells between 200 and 500 / ml) were included in the study. T-helper cells were filtered out of their blood, activated in the laboratory and treated with so-called zinc finger nucleases. These are restriction enzymes that can “cut out” specific DNA sequences - in this case the genetic code for the CCR5 receptor.

Removed coreceptors for binding of HIV to cell surface

After this intervention, the manipulated cells were returned to the patients in different doses (10, 20 and 30 million cells per infusion). After just 90 days, up to seven percent genetically modified CD4 was found in the blood and intestinal mucosa of the patients+Cells, which makes the researchers confident.

An approach that has been discussed for a long time is the activation of HIV expression in infected host cells. Various agents are currently being investigated to determine whether they are able to activate dormant HI proviruses. That means: Virus proteins have to be formed and appear on the surface of the cells so that they can be recognized by the immune system. Under the protection of simultaneous antiretroviral therapy, such forced virus expression should not lead to new infection of host cells. If necessary, the immune system should be supported by HIV-specific immune reagents (such as monoclonal antibodies in connection with the body's own complement components or cell toxins) to kill the HIV-infected cells and render released virus particles harmless.

Possible mechanisms to activate dormant HI proviruses are: the relaxation of chromatin by histone deacetylase inhibitors such as vorinostat, the activation of transcription factors (by NF-ƙB) and the activation of HIV mRNA elongation (by PTEF-b).

The “proof-of-principle” was achieved with the active ingredient vorinostat - developed for oncology - for this purpose, blood was taken from 16 test participants, their CD4+- Helper cells isolated and mixed with Vorinostat in the test tube. After six hours, gene expression in the cells of eleven test subjects was significantly upregulated. Eight of these eleven subjects then received the active ingredient directly orally. As a result, HIV gene expression increased by one and a half to ten times in all of them.

HI proviruses are actively taken from the "sleeper status"

There are numerous strategies in the “pipeline”, and perhaps, says Prof. Sharon Lewin from Monash University in Melbourne, President of the 2014 World AIDS Conference, several methods have to be combined or applied sequentially in order to ultimately achieve the goal. In any case, the global strategy launched in Washington has raised enormous hopes. When asked how long it will take for a possible cure, the Vice President of the American Foundation for AIDS Research, Prof. Rowenta Johnston, replied with a quote from Albert Einstein: "If we knew the answer, it wouldn't be research."

Dr. med. Vera Zylka-Menhorn

Mobile security laboratory tracks down HIV

A white truck with the label "mobile lab" tours through the Western Cape Province in South Africa, inside a safety laboratory of biological safety level 3 for handling highly infectious pathogens and the latest cryotechnology for freezing blood samples. The mission: to fight infectious diseases such as AIDS and tuberculosis on the spot, where the spread of these diseases is greatest, but the medical infrastructure is least available.

Photo: Fraunhofer-Gesellschaft

The mobile S3 laboratory is a development of the Fraunhofer Institute for Biomedical Technology in St. Ingbert and Sulzbach in Saarland and was realized with the Stellenbosch University / South Africa.

The challenge in the conception: The highly sensitive technology must function perfectly even in poor road and extreme climatic conditions. The laboratory manages without supply lines for electricity, water or sewage, so it can be operated independently. Access from the treatment room to the security area is through a security gate. Ultra-fine air filters and a pass-through autoclave with its own water circuit ensure that no pathogens get into circulation. There are two sterile workbenches and a sterilizer with vacuum steam sterilization for contaminated objects. Also on board is a cryobank with up to 300 liter liquid nitrogen-cooled containers for freezing infectious blood samples. You will receive an electronic chip to avoid mix-ups before they are frozen.

The S3 laboratory has an internet connection so that newly acquired data can be accessed online. Remote monitoring and control via satellite phone are possible. EB