Genome Scan Exposes HIV Infection Proteins

Molecular virologists have used the latest siRNA technology to interrogate the human genome one gene at a time in order to identify the host cell factors used by the AIDS virus to enter cells and commandeer the cells' protein synthetic machinery.

Investigators at the Salk Institute for Biological Studies (La Jolla, CA, USA) in collaboration with colleagues at the Burnham Institute for Medical Research (La Jolla, CA, USA) combined genome-wide siRNA analyses with interrogation of human interactome (cellular protein-protein interaction network) databases to assemble a host-pathogen biochemical map containing 213 confirmed host cellular factors and 11 HIV-1-encoded proteins.

Data published in the October 3, 2008, issue of the journal Cell revealed that after high throughput screening of more than 144,000 siRNAs it was possible to identify protein complexes that regulate ubiquitin conjugation, proteolysis, DNA-damage response, and RNA splicing as important modulators of early-stage HIV-1 infection.

Over 40 new factors were shown to specifically influence the initiation and/or kinetics of HIV-1 DNA synthesis, including cytoskeletal regulatory proteins, modulators of posttranslational modification, and nucleic acid-binding proteins. Another 15 proteins with diverse functional roles, including nuclear transport, prostaglandin synthesis, ubiquitination, and transcription, were found to influence nuclear import or viral DNA integration.

"HIV has just nine genes, coding for 15 proteins, compared to bacteria, which harbor several thousand genes, or humans, with over 20,000 genes,” said senior author Dr. Sumit K. Chanda, associate professor of infectious and inflammatory diseases at the Burnham Institute for Medical Research. "We have known for a long time that HIV hijacks our cellular proteins to complete its life cycle. This study now lays out its flight plan.”

This new understanding of the molecular relationship between host cell and the AIDS virus could lead to the development of a new class of HIV therapeutics aimed at disrupting the human-HIV interactions that lead to viral infection.

Related Links:
Salk Institute for Biological Studies
Burnham Institute for Medical Research