Why do you think your paper is highly cited?

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?

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 future?

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
M.I.T.
and Harvard University
Harvard Medical School
Boston, MA, USA

KEYWORDS: IMMUNODEFICIENCY-VIRUS TYPE-1; N-LINKED GLYCOSYLATION; ENDOPLASMIC-RETICULUM; NUCLEAR IMPORT; SNARE TLG1P; LATE GOLGI; COMPLEX; GLYCOPROTEINS; TRANSPORT; CXCR4.