No-entry Zones For AIDS Virus

The AIDS virus inserts its genetic material into the genome of infected cells. Scientists at the German Center for Cancer Research have now shown for the first time the virus spares almost exclusively specific sites in the human genetic material in this process. This finding may be useful for the development of new specific anti-AIDS drugs.


HIV particles in a cell membrane. (Credit: Prof. Dr. Hanswalter Zentgraf, German Cancer Research Center)

Like all retroviruses, the AIDS virus (HIV) integrates its DNA into the genome of infected cells.As integration sites, HIV usually prefers active genes transcribed often. This is advantageous for the virus, because here is where a large number of enzymes that are responsible for transcription. The abuses of this computer virus for their own cellular replication.

In DKFZ, Associate Professor (PD), Dr. Stephanie Laufs and Dr. Frank Giordano are trying to ascertain if the AIDS virus can be used as gene vectors in gene therapy. Therefore, it is crucial to know exactly where HIV integrates its genetic material into host cells. This is a critical step in gene therapy, since depending on the position, this process can result in permanent activation of oncogenes or other damage. Therefore, the researchers took a close look to begin an analysis of more than 46,000 known integration sites of HIV-based gene delivery vehicles that were identified in various studies of gene therapy or available in databases genes.

So far, researchers have been convinced that both HIV and delivery vehicles for HIV genes have a preference for sites where gene transcription begins. At these sites there is an abundance of enzymes that the virus needs. However, database analysis produced an entirely different picture. While HIV do many really integrate near transcription start sites, researchers found almost no starting point as the closest, close to sites of HIV integration, ie, only 1,000 building blocks DNA "left" and "right" for them.

"For the first time we have very clearly defined areas in the human genome where HIV is rarely integrated," says Giordano. Scientists are electrified by the result, because there must be a reason why HIV evades these sites. "We assume that there is a special mechanism at work that blocks the way for the virus," says Giordano. "On the other hand, it is possible that some factor that HIV needs for integration is not on these sites." Even researchers already know that this barrier of access can not be a nonspecific "even prefer other retroviruses to insert their genetic material, exactly at the sites of transcription initiation," says Laufs. "Therefore, we assume that the mechanism of protection of sites of initiation of transcription of active genes in the genome of HIV integration very specifically prevents the integration of HIV." For example, this mechanism could block the work of an enzyme called integrase, which is responsible for integrating the viral DNA into the infected cell DNA. 

This enzyme is located in the center of the search for better AIDS treatment. Highly active therapy attacks the virus available today from different angles using different drugs: reverse transcriptase inhibitors prevent viral genome copy. Protease inhibitors block the maturation of new viral proteins. Scientists agree, however, that the best way to combat the severe immune deficiency is to prevent the integration of viral genetic material into the DNA of host cells.Prevention of this substance, called integrase inhibitors have been used in recent years, but viruses have begun to escape its effects through mutations. Therefore, virologists is urgently seeking new approaches to blocking this key enzyme of the virus. The mechanism that prevents HIV integration in transcription start could be a molecular model for the development of such substances.