Hindering HIV

Courtesy of Devon Gregory and Marc Johnson

The paper:

S.J.D. Neil et al., “Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu,” Nature 451:425–30, 2008. (Cited in 96 papers)

The finding:

To be released from some cells, HIV-1 requires an accessory protein called Vpu, suggesting that these cells carry a host factor that inhibits the release of virions. To identify this mysterious antiviral molecule, virologist Paul Bieniasz of the Aaron Diamond AIDS Research Center at The Rockefeller University and his colleagues compared mRNA expression between cells in which HIV-1 needs Vpu and cells in which HIV-1 could be released without Vpu, to find the genes associated with the Vpu requirement. They found CD317.

The mechanism:

Bieniasz and his team nicknamed CD317 “tetherin” because of its suspected mode of action: forming a physical tether between the budding virus particle and the infected cell, which “prevents virions from infecting [distant] cells,” Bieniasz says. Last October, he showed that tetherin’s two lipid tips acted as anchors—one in the virus envelope and the other rooted in the host cell’s membrane (Cell 139:499–511, 2009).

The key piece:

Bieniasz’s group synthesized an artificial tetherin molecule with the same structure as tetherin but almost no sequence homology. The artificial molecule inhibited HIV release, demonstrating that it is the structure of tetherin—not the sequence—that supports its antiviral activity.

The others:

Scientists have identified two other innate antiviral proteins: Trim5a interferes with the uncoating of the virus, while APOBEC3G induces mutations in HIV’s genetic code, after which it cannot replicate. “So when tetherin came along, people kind of went ‘Aha, I get this,’” says University of Southern California virologist Paula Cannon. “It was just the latest in a growing group of restriction factors that have antiviral activities.”