Probing HIV's Dependence on Host Proteins

An important new study has just been published in Science Express, the advance online section of the widely read journal Science. Abraham Brass and colleagues report results obtained using a genome-wide screen for host proteins necessary for HIV replication. The researchers used an approach that involves blocking the activity of known human genes using small slices of RNA called small interfering RNAs (siRNAs). A staggering 21,121 pools of four siRNAs per gene were employed in the study, ultimately revealing 273 host proteins that appear necessary for efficient HIV replication (the researchers have dubbed them "HIV dependency factors" or HDFs).

Thirty-six HDFs comprise previously reported factors such as the CD4 and CXCR4 proteins, but the others are novel, including proteins involved in transporting materials into a cell's nucleus, glycosylation (addition of sugar molecules to proteins) and degradation of cellular proteins (autophagy). One identified protein, ZNRD1, was also implicated in a recent study of genomic associations with viral load set point in people with HIV (mutations in the gene for ZNRD1 were associated with slow progression). So much data was generated that much of it is not in the paper but in the supplemental online material that accompanies it. The authors also offer a busy schematic that gives a sense of the complex theater of virus-host interactions that they have raised the curtain on (click on the thumbnail for a larger image):

CREDIT: A. L. BRASS ET AL., SCIENCE

In an accompanying news story by Jon Cohen, a number of leading HIV researchers praise the paper and note that it offers a dazzling array of potential new leads for scientists looking to better understand the HIV life cycle, and how to inhibit it.

Published Online January 10, 2008
Science DOI: 10.1126/science.1152725

Submitted on November 7, 2007
Accepted on December 21, 2007

Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen

Abraham L. Brass 1, Derek M. Dykxhoorn 2{dagger}, Yair Benita 3{dagger}, Nan Yan 2, Alan Engelman 4, Ramnik J. Xavier 5, Judy Lieberman 2, Stephen J. Elledge 6*

1 Department of Genetics, Center for Genetics and Genomics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.; Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
2 Immune Disease Institute and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
3 Center for Computational and Integrative Biology, Harvard Medical School, Boston, MA 02114, USA.
4 Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA.
5 Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.; Center for Computational and Integrative Biology, Harvard Medical School, Boston, MA 02114, USA.
6 Department of Genetics, Center for Genetics and Genomics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.

{dagger}These authors contributed equally to this work.

HIV-1 exploits multiple host proteins during infection. We performed a large-scale siRNA screen to identify host factors required by HIV-1 and identified over 250 HIV-dependency factors (HDFs). These proteins participate in a broad array of cellular functions and implicate new pathways in the viral life cycle. Further analysis revealed previously unknown roles for retrograde Golgi transport proteins (Rab6 and Vps53) in viral entry, a karyopherin (TNPO3) in viral integration, and the Mediator complex (Med28) in viral transcription. Transcriptional analysis revealed that HDF genes were enriched for high expression in immune cells suggesting that viruses evolve in host cells that optimally perform the functions required for their life cycle. This effort illustrates the power with which RNA interference and forward genetics can be used to expose the dependencies of human pathogens such as HIV, and in so doing identify potential targets for therapy.

Comments

[Michael Linde]

This study should not be surprising. It is very easy to focus on viral factors and forget that HIV is an obligate intracellular parasite. As an RNA virus, HIV's genome is limited in size, encoding only a handful of viral proteins; the virus needs to subvert the normal cellular processes to be successful.

The involvement of host factors goes well beyond entry, trafficking and replication. Virions carry hundreds of different host proteins--look at a mass spectometry paper by Chertova and colleagues in the Journal of Virology from a couple of years ago and you'll see just loads of host proteins in the virus. The viral envelope looks more like an immunologic synapse than a virus.

Hopefully studies like these will spur more interest in the HIV-host factor interplay. I still see a glaring lack of interest in this regard in the vaccine and drug development fields. Even in the basic science labs, most people do not work on host factors (well, if you exclude APOBEC). Host factors will be easier to target than viral factors and my own personal belief is that if we target viral factors, the virus will always win.