Retroviral DNA Findings May Lead to Better Therapies for HIV Infection

    When retroviruses such as HIV infect a cell, they first make a copy of their RNA genome in the form of DNA. The relatively short viral DNA strand then moves to the cell nucleus, where it inserts itself into the host cell’s DNA.

    Scientists at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute say they discovered how retroviral DNA insertion complexes hunt for a suitable spot in a cell nucleus and how quickly insertion happens at the chosen site. They believe their findings could help improve treatments for HIV infection and make gene therapy safer and more efficient.

    The researchers, who published their study (“Retroviral Intasomes Search for a Target DNA by 1D Diffusion Which Rarely Results in Integration”) in Nature Communications, used prototype foamy virus integrase as a model and two molecular microscopy techniques to record viral integration complexes traveling along stretches of target DNA in search of insertion points. Integration complexes consist of viral DNA plus the enzymes that insert it into the host DNA.

    The integration complexes moved along the target DNA for distances of 1500 DNA base pairs for periods of 2–3 seconds. When they found a suitable spot, insertion of the viral DNA happened in less than a half second.

    “We were surprised that the enzyme complex does so much searching,” says co-corresponding author Kristine Yoder, Ph.D, assistant professor of molecular virology, immunology and medical genetics. “Searching 1.5 kilobases of DNA is quite a distance, and 2–3 seconds is a long time in molecular terms to remain associated with the DNA.”

    Their data also showed that the viral integration complexes move along DNA like a nut on a bolt rather than sliding along like a washer. According to Dr. Yoder, the findings are important.

    “The integration of retroviral DNA is a relatively uncommon event compared with the number of viral DNA copies found in infected cells. If we can understand why insertion doesn’t occur more often, it might lead to new drugs that prevent retroviral infection,” she explained. “Our study suggests that the problem lies in the search for an insertion site and not the insertion itself. In addition, gene therapy involves searching and insertion events, so our findings might help make that process more efficient.”