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Intrinsic host defenses against HIV-1

Wednesday, October 8, 2014

Speaker

Paul D. Bieniasz, Ph.D.
Professor
HHMI Investigator
Aaron Diamond AIDS Research Center

Dr. Bieniasz received his undergraduate degree in biochemistry from the University of Bath, UK, in 1990 and his Ph.D. in virology from Imperial College, University of London, in 1996. He became a professor at Rockefeller University in 2010, where his is head of the laboratory of retrovirology.Dr. Bieniasz has been active in several areas of HIV-1 research. As a post-doctoral fellow with Bryan Cullen, he was among the first to determine sites of interaction between the HIV-gp120 envelope proteins and the CCR5 co-receptor. He also showed that a species-dependent block to HIV-1 transcription in rodents arose as a result of a single amino acid difference in the cyclin T component of the P-TEFb transcription factor.In his own laboratory, Dr. Bieniasz has worked on many aspects of retrovirus replication. In the area of HIV-1 particle assembly, his lab showed that various components of ESCRT pathway and ubiquitin ligases are required for the budding and release of retrovirus and filovirus particles from infected cells. With collaborators, the Bieniasz lab was the first to image the genesis of single viral particles in living cells, revealing the dynamics of the assembly of individual HIV-1 virions, as well as how viral RNA genomes and the ESCRT proteins are recruited during particle assembly and release. More recently, his laboratory has redefined the rules that govern how HIV-1 packages it genome into virions.In the area of innate antiviral defenses, the Bieniasz lab’s early work showed that mammalian cells possess an antiretroviral activity that targets the capsids of incoming retroviruses, , including HIVs and SIVs. A major subsequent finding by his group was the discovery of a broad-spectrum antiviral protein (Tetherin) that blocks viral particle release, along with the finding that Tetherin is antagonized by HIV-1 Vpu and SIV Nef proteins. Dr. Bieniasz’s group have also described the molecular mechanism by which tetherin inhibits virion release. Most recently, his group co-discovered that an interferon-induced protein, Mx2, has anti-HIV-1 activity, apparently by blocking HIV-1 entry into the nucleus.Dr. Bieniasz was a 2003 recipient of the Elizabeth Glaser Scientist Award from the Elizabeth Glaser Pediatric AIDS Foundation and the 2010 recipient of the Eli Lilly and Company Research Award.

Summary

The investigation of impeded viral replication in animal cells of particular types or species has uncovered great complexity in the interaction between retroviruses and their hosts. These studies have revealed that cells are equipped with a diverse set of proteins that can directly inhibit the replication of retroviruses, including HIV-1. Genes encoding antiretroviral proteins exhibit unusually high sequence variation, presumably because selection pressures exerted by ancient viral infections have caused them to evolve at an unusually rapid pace. The adaptation of modern retroviruses to specific variants of antiviral proteins has resulted in viral specialization to particular host species and the creation of formidable barriers to replication in other species. These phenomena likely protect humans from infection by some modern retroviruses, but have also impaired the development of animal models of HIV-1 infection. In this lecture, Dr. Bieniasz will describe his studies of Tetherin, an antiviral protein that inhibits the release of diverse virus particles from infected cells and Mx2, an antiviral protein that apparently blocks the entry of HIV-1 into the nucleus. Finally, he will describe his laboratory’s attempts to break antiviral protein-imposed barriers to cross-species transmission of HIV-1 in order to generate better animal models of human AIDS.


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