The protein is 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,” said Dr Frederic Bushman, professor of microbiology at Penn.
The study demonstrates the first piece of a mechanism that dictates where HIV integration takes place. Previous studies at other institutions have shown that LEDGF binds tightly to HIV integrase, the enzyme that is important for the integration reaction. Now, the Penn researchers have shown 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.
“This is first example of a cellular factor that’s a clear player in target site selection,” said Dr Bushman. “This isn’t engineering yet, but it’s a key piece of information on the way.”