Featured Research

from universities, journals, and other organizations

Pathogenic landscape of HIV: Hundreds of connections between viral and human proteins identified in work that may reveal new drug targets

Date:
January 12, 2012
Source:
University of California - San Francisco
Summary:
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.

How HIV Interacts with Human Cells. HIV is a virus with a small genome and very few proteins of its own. It survives in the human body by invading human cells and hijacking host proteins. A recent UCSF-led study identified nearly 500 human proteins with which HIV interacts. Some of these interactions may be viable new targets for drug design.
Credit: Image courtesy of University of California - San Francisco

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.

Related Articles


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. Drawing upon the expertise of several laboratories that are world leaders in this area of research, 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.

"These papers represent a truly collaborative effort from many different groups from several universities," Krogan said, "The multi-disciplinary nature of this work is key if we are to tackle problems of this magnitude."

Unlocking the Doors to HIV Drug Design

Understanding the details of how HIV works within human cells and finding ways to interfere with those processes are two of the central questions scientists start with when designing drugs to treat people with HIV/AIDS.

The virus is small and has only a tiny amount of genetic material in its own genome -- about 10,000 times less DNA than that of the human genome. Where typical human cells may include thousands of different proteins, HIV brings fewer than 20 of its own. Once inside a human cell, however, the virus relies extensively on the existing molecular machinery found there, hijacking the function of some human proteins, shutting down others and subverting still more.

HIV is remarkably effective at this. In the last 30 years, the virus has infected tens of millions worldwide. The World Health Organization estimates some 34 million people are currently living with the virus and that HIV has already claimed some 25 million lives.

One of the greatest success stories in the last few decades has been the development of powerful antiretroviral drugs that block the action of various viral proteins essential to HIV's lifecycle. Since the 1990s, the standard of treatment for people with HIV/AIDS has been therapy that combines several of these drugs. The availability of such drug combinations worldwide has allowed millions of people with the disease to live longer.

The UCSF-led study has provided the most comprehensive and detailed picture to date of all the interactions HIV has with the human cells it infects, and identifying these interactions may lead to the development of new drugs to treat the disease.

Of the 497 specific interactions between HIV and human proteins discovered in the new work, only 19 of those were previously reported. What accounts for the discrepancy, Krogan said, is that this was the first study to look for such interactions globally and in an unbiased fashion -- unlike previous studies, which had been more focused. The work involved expressing every HIV protein in a series of human cells, pulling these viral proteins out of the cells, analyzing them with a method known as mass spectrometry and looking for the associated human proteins.

To illustrate the potential significance of these new associations, Krogan and his colleagues explored one of them in depth in the second paper: an association between an HIV protein called Vif and CBF-β, a human protein.

Vif is known to target for degradation the restriction factor APOBEC3G, a host factor that protects cells from HIV infection. Krogan and colleagues show that the transcription factor CBF-β associates with Vif and is needed for Vif to counteract APOBEC3G. Previously no one had known CBF-β collaborated with Vif to play such a role, Krogan said, and interfering with this association may be a way to block the virus. Ultimately, if scientists can design compounds to do this safely and effectively, those compounds could form the basis for a new type of HIV/AIDS treatment.


Story Source:

The above story is based on materials provided by University of California - San Francisco. The original article was written by Jason Socrates Bardi. Note: Materials may be edited for content and length.


Journal References:

  1. Stefanie Jδger, Peter Cimermancic, Natali Gulbahce, Jeffrey R. Johnson, Kathryn E. McGovern, Starlynn C. Clarke, Michael Shales, Gaelle Mercenne, Lars Pache, Kathy Li, Hilda Hernandez, Gwendolyn M. Jang, Shoshannah L. Roth, Eyal Akiva, John Marlett, Melanie Stephens, Ivan D’Orso, Jason Fernandes, Marie Fahey, Cathal Mahon, Anthony J. O’Donoghue, Aleksandar Todorovic, John H. Morris, David A. Maltby, Tom Alber, Gerard Cagney, Frederic D. Bushman, John A. Young, Sumit K. Chanda, Wesley I. Sundquist, Tanja Kortemme, Ryan D. Hernandez, Charles S. Craik, Alma Burlingame, Andrej Sali, Alan D. Frankel, Nevan J. Krogan. Global landscape of HIV–human protein complexes. Nature, 2011; DOI: 10.1038/nature10719
  2. Stefanie Jδger, Dong Young Kim, Judd F. Hultquist, Keisuke Shindo, Rebecca S. LaRue, Eunju Kwon, Ming Li, Brett D. Anderson, Linda Yen, David Stanley, Cathal Mahon, Joshua Kane, Kathy Franks-Skiba, Peter Cimermancic, Alma Burlingame, Andrej Sali, Charles S. Craik, Reuben S. Harris, John D. Gross, Nevan J. Krogan. Vif hijacks CBF-β to degrade APOBEC3G and promote HIV-1 infection. Nature, 2011; DOI: 10.1038/nature10693

Cite This Page:

University of California - San Francisco. "Pathogenic landscape of HIV: Hundreds of connections between viral and human proteins identified in work that may reveal new drug targets." ScienceDaily. ScienceDaily, 12 January 2012. <www.sciencedaily.com/releases/2011/12/111221140349.htm>.
University of California - San Francisco. (2012, January 12). Pathogenic landscape of HIV: Hundreds of connections between viral and human proteins identified in work that may reveal new drug targets. ScienceDaily. Retrieved December 17, 2014 from www.sciencedaily.com/releases/2011/12/111221140349.htm
University of California - San Francisco. "Pathogenic landscape of HIV: Hundreds of connections between viral and human proteins identified in work that may reveal new drug targets." ScienceDaily. www.sciencedaily.com/releases/2011/12/111221140349.htm (accessed December 17, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Wednesday, December 17, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

UN: Up to One Million Facing Hunger in Ebola-Hit Countries

UN: Up to One Million Facing Hunger in Ebola-Hit Countries

AFP (Dec. 17, 2014) — Border closures, quarantines and crop losses in West African nations battling the Ebola virus could lead to as many as one million people going hungry, UN food agencies said on Wednesday. Duration: 00:52 Video provided by AFP
Powered by NewsLook.com
When You Lose Weight, This Is Where The Fat Goes

When You Lose Weight, This Is Where The Fat Goes

Newsy (Dec. 17, 2014) — Can fat disappear into thin air? New research finds that during weight loss, over 80 percent of a person's fat molecules escape through the lungs. Video provided by Newsy
Powered by NewsLook.com
Why Your Boss Should Let You Sleep In

Why Your Boss Should Let You Sleep In

Newsy (Dec. 17, 2014) — According to research out of the University of Pennsylvania, waking up for work is the biggest factor that causes Americans to lose sleep. Video provided by Newsy
Powered by NewsLook.com
Flu Outbreak Closing Schools in Ohio

Flu Outbreak Closing Schools in Ohio

AP (Dec. 17, 2014) — A wave of flu illnesses has forced some Ohio schools to shut down over the past week. State officials confirmed one pediatric flu-related death, a 15-year-old girl in southern Ohio. (Dec. 17) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins