Stephen J. Elledge &
Abraham L. Brass talk with ScienceWatch.com and
answer a few questions about this month's Fast Moving Front
in the field of Multidisciplinary. The authors have also
sent along images of their work.
Article: Identification of host proteins required
for HIV infection through a functional genomic
AL;Dykxhoorn, DM;Benita, Y;Yan, N;Engelman,
Journal: SCIENCE, 319 (5865): 921-926 FEB 15 2008
Addresses: Harvard Univ, Sch Med, Howard Hughes Med Inst,
Brigham & Womens Hosp,Dept Genet,Ctr Genet & Geno,
Boston, MA 02115 USA.
Harvard Univ, Sch Med, Howard Hughes Med Inst, Brigham
& Womens Hosp,Dept Genet,Ctr Genet & Geno, Boston,
MA 02115 USA.
Harvard Univ, Sch Med, Massachusetts Gen Hosp,
Gastrointestinal Unit, Boston, MA 02114 USA.
(addresses have been truncated)
Why do you think your paper is highly
This was the first systematic analysis of the function of human proteins in
the HIV life cycle. Abraham Brass of Massachusetts
General Hospital and I, along with our close collaborators, Judy
Leiberman and Ramnik Xavier of Harvard Medical School, used
state-of-the-art genetics and bioinformatics methods to explore this
pathogen's requirements, and identified hundreds of proteins involved in
the process, HIV-dependency factors (HDFs).
Furthermore, by uniquely employing a high-throughput titering assay, we
found HDFs involved in the complete viral lifecycle, all the way from HIV
entry through to reinfection by newly made viruses.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
Abraham L. Brass.
HIV dependency factors.
We used modern genetic methods based on RNA interference technology to turn
off human genes one at a time, and asked whether that gene was needed for
HIV to infect and proliferate in human cells.
By examining the entire genome, we were able to develop a high-resolution
map of the HIV life cycle with respect to the human proteins it hijacks.
Among some of the specific discoveries we made using this approach were
that the host nuclear importer, TNPO3, helps HIV access our genomes, and
that the cellular recycling program, called the autophagy pathway, was
needed by HIV.
It is also significant in that it showed that we can now use the power of
genetics to locate viral weaknesses, in a similar way to how the virus uses
genetics to avoid our immune system and gain resistance to drug
therapies—that is, we started to "turn the genetic tables" on HIV.
Would you summarize the significance of your paper
in layman's terms?
The significance of this study was that we now have a list of the parts of
a human cell that HIV depends upon in order to grow. These new proteins
could be targets for drugs that would prevent HIV, and possibly other
viruses, from infecting humans.
How did you become involved in this research and
were any particular problems encountered along the way?
We became involved in this work because we had developed a genetic
methodology and wanted to apply it to problems that are quite important as
regards human health and disease.
Where do you see your research leading in the
Through a grant from the Bill and Melinda Gates Foundation,
we plan to produce a much more detailed analysis of the human proteins
involved in HIV replication. We have also expanded our work to other
viruses and have identified host factors important for
hepatitis C virus,
West Nile Virus, and influenza A virus.
Do you foresee any social or political implications
for your research?
We think that this work has forced other groups, such as
those affiliated with industry, to publish their work on host dependency
factors. We have also raised the notion that host proteins could be good
antiviral targets. So far, the vast majority of drugs for viruses are aimed
at the virus itself.
HIV rapidly mutates to become resistant to these drugs. However, it the
drug target is a host protein, the virus cannot easily get around that. We
hope that more serious attention will soon be devoted to discovering drugs
for host factors which may inhibit viruses of all kinds.
Dr. Stephen J. Elledge
Department of Genetics
Center for Genetics and Genomics
Harvard Medical School
Boston, MA, USA Web
Dr. Abraham L. Brass
Ragon Institute of Massachusetts General Hospital
and Harvard University
Harvard Medical School
Boston, MA, USA