An international team of
researchers, led by scientists from the Francis Crick Institute and
Imperial College London, has discovered important new detail on how
retroviruses take over healthy cells.
The research may eventually lead to
more effective treatments to suppress the virus in people who have
been infected.
Retroviruses, such as HIV, insert
their genomes into the chromosomes of host cells, an irreversible
process which makes them particularly difficult to eradicate. The
viral enzyme responsible for this process is called integrase and
it is carried by every retrovirus. Using a very powerful electron
microscope, the research team discovered how integrase captures
tightly wound packages of human DNA called nucleosomes, in order to
insert the viral DNA.
Dr Peter Cherepanov, from the
Francis Crick Institute and Imperial College London, said:
"Cellular DNA is tightly packaged in the form of nucleosomal
arrays, with each nucleosome acting as a tiny reel. This compaction
could be expected to present an obstacle for viral integration. In
the course of this study, we were able to explain how the virus
captures and opens -up human nucleosomes to insert its DNA into a
human chromosome.
"The more we learn about the rules
of engagement between the viral integration machinery and host
cells, the easier it will become for us to break the chain of
events that lead to persistent infection. This can lead to more
effective antiretroviral drugs to treat HIV infection.
"There is also a potential benefit
for gene therapy. The unique ability of retroviruses to efficiently
integrate their genetic material into host cell chromosomal DNA
means they could be used to deliver highly targeted drugs as part
of gene therapy. However, uncontrolled integration by retroviruses
carries the risk of serious side effects. Understanding how to
selectively direct integration will potentially aid the development
of safer gene therapy."
Another Francis Crick Institute
investigator, Dr Alessandro Costa, explained how the
integrase-nucleosome complex was visualised: "Starting from 2D
images of individual molecular assemblies, we have reconstructed a
high-resolution 3D view of integrase attacking a tiny fragment of a
human chromosome, 10 billionths of a metre in diameter. This
achievement, inconceivable only four years ago, was made possible
by using a very sophisticated electron microscope, new generation
cameras and innovative software for data analysis.
"Biological nanomachines such as
integrase can now be imaged in unprecedented detail as they perform
their work. Thanks to these new tools we can rethink the way we ask
scientific questions".
Sir Paul Nurse, director of the
Francis Crick Institute, said: "This is a fascinating and important
discovery which increases our understanding of the way retroviruses
work. It has important long-term implications, not only for leading
to improvements in HIV treatments but also for treating a range of
other diseases which may benefit from gene therapy."
The paper Structural basis for
retroviral integration into nucleosomes is
published in Nature.