A human DNA-associated protein called LEDGF is the first such molecule found to control the location of HIV integration in human cells, according to a new study from researchers at the University of Pennsylvania School of Medicine. This study, published in this week's early online edition of Nature Medicine, describes the first clear target for modulating where viruses insert into the human genome, which has implications for better design of gene-therapy delivery. Retroviral vectors are often used to introduce therapeutic genetic sequences into human chromosomes, such as in the delivery of Factor VIII for hemophilia patients.

HIV integrates into active transcription units on chromosomes within the nucleus of human cells. These units are sites that lead to efficient expression of the viral genome. Most HIV-infected cells in a patient will have a very short life span, a day or less. "We surmise that this strategy helps the virus make hay while the sun is shining, as it were, producing lots of viral copies during a short time, so that the virus can maximize production of daughter virions," says Frederic Bushman, PhD, Professor of Microbiology at Penn.

This present study demonstrates the first piece of a mechanism that dictates where HIV integration takes place. Previous studies at other institutions showed that LEDGF binds tightly to HIV integrase, the enzyme that's important for the integration reaction. Now, Penn researchers showed in this study that the way LEDGF binds to HIV integrase and to specific sites on chromosomes suggests that HIV targets integration using a molecular tether.

Retroviruses contain RNA in their particles. They enter a cell and convert RNA into DNA by the enzyme reverse transcriptase and then integrate that DNA copy into the DNA of the host, using the integrase enzyme. The new viral particles are made by transcription of the viral genome, as with any cellular genes. If the cell divides, the viral DNA is copied and in
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
27-Nov-2005

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