Paul Bieniasz, Ph.D.
Investigator, Howard Hughes Medical Institute
The biology and evolution of viruses and eukaryotes are closely linked. Bieniasz seeks to define how host genes influence the replication of viruses, with an emphasis on human and primate immunodeficiency viruses. His lab seeks to characterize the host functions that viruses mimic, manipulate, and otherwise exploit, as well as the defenses cells have evolved against viral infection.
The consequences of viral infection are diverse, and range from lethal disease to beneficial insertion of viral genes into the host genome. In addition to determining the functions of viral genes and proteins, Bieniasz’s research seeks to define how the replication of viruses is influenced by host genes and pathways. Some host functions are manipulated or exploited by viruses to enable their replication, while others have arisen specifically to curtail virus infection.
One aspect of Bieniasz’s work is to define how virus components interact with host proteins to facilitate virus replication. His work, using biochemical, genetic, and imaging approaches, has revealed many details of the HIV-1 particle assembly process, including the recruitment of host proteins that drive assembly and particle budding. He is also interested in defining how HIV-1 viral RNA splicing, stability, transport, translation, and packaging into virions are regulated, as well as the fate and role of viral components following the entry of HIV-1 particles into target cells.
Another major area of interest is the arsenal of intrinsic host defenses against viruses. Throughout their evolution, eukaryotic organisms have frequently been colonized by viruses, and selection pressures imposed by ancient viral infections are likely responsible for shaping the array of intrinsic host defense mechanisms that influence susceptibility to modern viruses such as HIV-1. The Bieniasz lab works on several types of intrinsic defenses to understand the mechanistic details by which they inhibit virus replication. Two such inhibitors, discovered in the Bieniasz lab, include tetherin, which inhibits the release of a wide range of enveloped viruses from the surface of infected cells, and Mx2, which targets the capsid of HIV-1 to inhibit viral entry into the nucleus of target cells. The Bieniasz lab has shown that species-dependent differences in antiviral proteins are critical determinants of HIV-1 host range, and they have used this information to engineer improved animal models of AIDS virus infection in monkeys, which should provide testing grounds for new forms of therapy and prevention. The Bieniasz lab is currently discovering and investigating new types of defenses against HIV-1 and other viruses and the mechanisms by which they work. For example, the lab recently found that mammalian cells can deplete viral RNA molecules that are recognized as foreign based on their nucleotide composition. They are also conducting a variety of investigations into the nature of innate and adaptive immunity to SARS-CoV-2, including the development of techniques to identify protective antibodies and therapeutics.
In addition to his work on modern viruses, Bieniasz has pioneered the field of “paleovirology,” which explores how ancient viruses impacted the evolution of their hosts. Mammalian genomes contain a fossil record of viral DNA from extinct retroviruses that infected the germ cells of ancient mammalian ancestors, and the Bieniasz Lab has reconstituted functional viruses and proteins encoded by this ancient viral DNA. The lab also seeks to understand how ancient retroviruses were extinguished, which may give clues about how to combat modern viral infections.