Pathogenic Landscape Of HIV

In perhaps the most comprehensive survey of the inner workings of HIV, an international team of scientists led by researchers at the University of California, San Francisco has mapped every apparent physical interaction the virus makes with components of the human cells it infects-work that may reveal new ways to design future HIV/AIDS drugs.

Explored this week in back-to-back papers in the journal Nature, the survey reveals a pathogenic landscape in which HIV's handful of proteins makes hundreds of physical connections with human proteins and other components inside the cell.

In one paper, the team details 497 such connections, only a handful of which had been previously recognized by scientists. Disrupting these connections may interfere with HIV's lifecycle, and the existence of so many new connections suggests there may be several novel ways to target the virus.

"Have we identified new drug targets?" said Nevan Krogan, PhD, who led the research. "I believe we have."

Krogan is an associate professor of Cellular and Molecular Pharmacology at UCSF and an affiliate of the California Institute for Quantitative Biosciences (QB3). He is also a faculty member at the UCSF - affiliated J. David Gladstone Institutes in San Francisco. Stefanie Jager, the lead author from the Krogan lab, collaborated with several other labs in the UCSF School of Medicine and the UCSF School of Pharmacy - including those of Andrej Sali, Alan Frankel, Charles Craik, Alma Burlingame, Ryan Hernandez and Tanja Kortemme - to carry out the global analysis.

In a companion paper, Krogan and collaborating labs of John Gross (UCSF) and Reuben Harris (University of Minnesota) investigated one such connection in detail. They discovered that an HIV protein called Vif makes a physical connection with a human protein called CBF-β, hijacking its function. This virus requires this action to function, said Krogan, which suggests that disrupting the connection may be a viable way to design new HIV/AIDS therapies.

"This is a good example of how biophysical studies can improve our understanding of disease and point the way to the exploration of potential therapeutic targets," said Judith H. Greenberg, PhD, acting director of the National Institute of General Medical Sciences (NIGMS).

NIGMS and the National Institute of Allergy and Infectious Diseases (NIAID), both components of the National Institutes of Health, partially funded this work through three large structural and systems biology program grants to UCSF-called HARC (HIV Accessory and Regulatory Complexes) (PI: Alan Frankel, UCSF), HINT (HIV Innate Networks Team) (PI: John Young, Salk Institute) and the Center for Systems and Synthetic Biology (PI: Wendell Lim, UCSF). The work was also funded by NIH's National Center for Research Resources, QB3 and through a Searle Scholarship and a Keck Young Investigator Award. Several of the researchers are also associated with the Host Pathogen Circuitry Center at UCSF.