Like all retroviruses, the AIDS virus (HIV) integrates its DNA into the genome of the infected cell. As integration sites, HIV usually prefers active genes that are transcribed frequently. This is advantageous for the virus, because this is where it finds large amounts of enzymes which are responsible for transcription. The virus abuses this cellular equipment for its own replication.
At DKFZ, Associate Professor (PD) Dr. Stephanie Laufs and Dr. Frank Giordano are trying to find out whether AIDS viruses can be used as gene delivery vehicles in gene therapy. Therefore, it is crucial for them to know where exactly HIV integrates into the genetic material of the host cell. This is a critical step in gene therapy, because depending on the position, this process can result in permanent activation of oncogenes or other damage. Therefore, the researchers took a very close look by starting an analysis of more than 46,000 known integration sites of HIV-based gene delivery vehicles that were determined in various gene therapy studies or are available in gene databases.
Up to now, researchers have been convinced that both HIV and HIV gene delivery vehicles have a particular preference for sites where gene transcription starts. At these sites there is an abundance of those enzymes which the viruses need. However, the database analysis produced an entirely different picture. While many HIV do really integrate close to transcription start sites, the investigators found hardly any such start points in the closest, immediate vicinity of the HIV integration sites, i.e. only 1,000 DNA building blocks "to the left" and "to the right" of them.
"For the first time we have very precisely defined areas in the human genome where HIV hardly ever integrates," Giordano explains. The scientists are electrified by the result, because there must be a reason why HIV evades these sites. "We assume that there is a particular mechanism at work which blocks the way for the virus," says Giordano. "On the other hand, it is also possible that some factor that HIV needs for its integration is missing at these sites." The researchers even know already that this access barrier cannot be an unspecific one: "Other retroviruses even prefer to insert their genetic material exactly at the transcription start sites," Laufs explains. "Therefore, we assume that the mechanism protecting the transcription start sites of active genes from HIV genome integration very specifically prevents HIV integration." For example, this mechanism might block the work of an enzyme called integrase, which is responsible for integrating the viral DNA into the DNA of the infected cell.
This enzyme is currently in the focus of the search for an improved AIDS therapy. The highly active treatment available today attacks the virus from several different angles using different drugs: Reverse transcriptase inhibitors prevent the viral genome from being copied. Protease inhibitors block the maturation of new viral proteins. Scientists agree, however, that the best way of fighting the severe immune deficiency is to prevent integration of the viral genetic material into the DNA of the host cells. Substances preventing this, called integrase inhibitors, have been used in recent years, but the viruses have already started evading their effect through mutations. Therefore, virologists are urgently searching for new approaches to blocking this key enzyme of the virus. The mechanism that prevents HIV from integrating at the transcription start site might be a molecular model for developing such substances.A picture is available at:
Dr. Sibylle Kohlstaedt | EurekAlert!
Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory
Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP
Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.
Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
09.12.2016 | Life Sciences
09.12.2016 | Ecology, The Environment and Conservation
09.12.2016 | Health and Medicine