Pitt Research Breakthrough Finds Weak Link to Disrupt AIDS Development

In order for HIV to proliferate and infect new cells in the body, a number of proteins need to interact with each other in just the right way. If they don't, the virus is not able to multiply and spread, and HIV infection cannot develop into full-blown Auto Immune Deficiency Syndrome (AIDS). It's a case of finding a weak link and exploiting its potential to disrupt an entire supply chain. In the University of Pittsburgh microbiology lab of Dr. Thomas Smithgall, this protein sabotage approach has successfully allowed them to identify a helper molecule that, if compromised, could form the basis of an effective new HIV/AIDS treatment therapy. The paper documenting their research appeared in the January 24 issue of Chemistry & Biology.

[Graphic courtesy of Chemistry & Biology paper]

The team started with a protein called Nef, which they knew from previous research was a critical AIDS progression factor, as it helps other proteins to get around in the cell while evading the body's immune system response. To track this helper protein, they linked it to an enzyme called Hck, which is activated by Nef in HIV-positive cells. Their thinking was that something that prevented Nef from carrying out its usual business could potentially keep HIV from replicating as well. They designed an automated screening procedure to test hundreds of thousands of compounds for their ability to block Nef activity, and came up with a strong candidate, called B9.

The next step was to find out more about how B9 worked. Subsequent tests showed that B9 interfered with the ability of two Nef molecules to dimerize, or become a new chemical structure by bonding.  Without that step, the chain of events was broken. According to Smithgall, from a Pitt news release:

“This pocket where B9 binds to Nef and where Nef forms a dimer indicates it’s a hot spot, or Achilles heel, that could represent a new target for HIV drugs. Our test tube and cell culture experiments show that blocking this site brings HIV replication to a halt.”

The Smithgall research team is now working with colleagues at the University of Pittsburgh Drug Discovery Institute (UPDDI) to further explore B9 for its therapeutic potential for the prevention of AIDS. According to a recent UPDDI news release, 4 other HIV research projects at Pitt have just received a total of $11M of funding from the Bill and Melinda Gates Foundation. Those research projects will explore:

• a new detection blood test that can catch infection at an earlier stage
• the prevention of HIV infection through monthly injections of a treatment drug
• the influence of hormonal contraception on HIV infection
• the feasibility of thin film dosage forms for 3rd world distribution

[View of the Univ of Pittsburgh campus from the 35th floor of the iconic Cathedral of Learning building, courtesy of wikipedia]

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