Mapping HIV-human protein to protein interaction reveals new targets for better drug design

HIV has a small genome (roughly 9,000 bases) and it survives by using the host's proteins and DNA. Understanding how these proteins come in contact and interact with one another is crucial in order to unravel the mechanisms by which HIV hijacks the cellular machinery and proliferates. A comprehensive work [1] by a group of researchers at UCSF lead by Nevan Krogan looked at two human cell lines in particular and identified 497 HIV-human protein-protein interactions between 16 HIV proteins and 435 human factors. The study, published in the last issue of Nature, is the first one to look at protein-protein interactions in a host-pathogen system, and it opens up new possible targets for drug design.

The researchers devised a score to classify the strength of the interactions, which they statistically validated through random reshuffling. They identified 196 interactions in both cell types, while 150 and 151 were specific to each line (HEK293 and Jurkat cells respectively, two human cell lines that were isolated in the '70s and are used today in experiments). Interestingly, the proteins identified in both cell lines had stronger evolutionary signatures than the others, something the researchers were able to identify using comparative genomics between human and rhesus macaque.

Besides revealing an enrichment for host proteins that the virus recruits in order to replicate, the study unveiled proteins that have an inhibitory role during the infection. For example, they knocked down ten interactors using RNAi and observed an increase in HIV infection, suggesting that those factors may play a role in inhibiting replication.

"Ultimately, our analysis of the host factors co-opted by different viruses using the same proteomic pipeline will allow for the identification of protein complexes routinely targeted by different pathogens, which may rep- resent better therapeutic targets for future studies."

[1] Jäger, S., Cimermancic, P., Gulbahce, N., Johnson, J., McGovern, K., Clarke, S., Shales, M., Mercenne, G., Pache, L., Li, K., Hernandez, H., Jang, G., Roth, S., Akiva, E., Marlett, J., Stephens, M., D’Orso, I., Fernandes, J., Fahey, M., Mahon, C., O’Donoghue, A., Todorovic, A., Morris, J., Maltby, D., Alber, T., Cagney, G., Bushman, F., Young, J., Chanda, S., Sundquist, W., Kortemme, T., Hernandez, R., Craik, C., Burlingame, A., Sali, A., Frankel, A., & Krogan, N. (2011). Global landscape of HIV–human protein complexes Nature DOI: 10.1038/nature10719

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