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2015 Distinguished Research Career Award

Dr. Paul Bieniasz’s research program addresses the conundrum that mammalian cells are well-equipped to inhibit virus replication, yet human retroviruses ultimately win the virus-host standoff. Using tools of molecular virology, genetics and genome-wide discovery, Dr. Bieniasz’s research explores the basic mechanisms underlying retrovirus-host interactions, focusing on how HIV and related viruses replicate in cells. By identifying several host proteins necessary to promote or prohibit the replication of retroviruses, Dr. Bieniasz has taken strides toward understanding the molecular basis for HIV/AIDS.

In discovering the host defense molecule Tetherin, Dr. Bieniasz’s research uncovered a previously unknown host activity: the formation of protein-based tethers that cause retention of fully formed HIV-1 particles on infected cell surfaces. Overcoming this restriction to spreading infection is Vpu, an HIV-1 encoded antagonist of Tetherin and thereby promotes the release and dissemination of HIV-1 particles from Tetherin-expressing cells.

The Bieniasz group determined ubiquitin ligases and components of the class E vacuolar protein-sorting pathway induce the fusion of virus and cellular membranes, promoting the release of nascent virus particles. The evaluation of HIV-1 RNA binding activity in cells and virions using cross-linking and RNAseq approaches revealed functional distinction in viral RNA binding activity: in the cytoplasm, Gag is bound to RNA sequences rich in guanine, but at the plasma membrane, Gag binding behavior changed to favor HIV’s unusual adenine – rich sequence bias. Thus, Bieniasz’s screening approach is unveiling the relationship of viral RNA sequence bias to assembly of infectious HIV-1.

Another antiretroviral protein, myxovirus resistance 2 (MX2), was identified by Dr. Bieniasz’s comparative gene expression profiling of cells that differ in the activity of interferon-induced genes to inhibit virus replication. MX2 was identified to inhibit the ability of the virus to generate a provirus, the DNA form of the retrovirus, that is essential to complete the virus life cycle. MX2 inhibits HIV-1 infection by inhibiting capsid-dependent nuclear import of the subviral complex containing the reverse transcribed DNA.

Converting fundamental discoveries into practical benefits is an overarching goal of Dr. Bieniasz and his colleagues; in particular, they are working toward the goal of a better animal model of human AIDS. By engineering and adapting specific components of HIV-1 to avoid or inactivate the growing list of host restriction factors, including TRIM5 and APOBEC3, his group successfully derived simian cell tropic HIV-1 strain (stHIV-1). The generation of HIV-1 strains that can replicate in monkeys would be of enormous practical benefit and would likely revolutionize preclinical studies of HIV-1 drugs and vaccines.

Dr. Paul Bieniasz (right) receives Career Award crystal from Center for Retrovirus Research Director Dr. Patrick L. Green (left).

Dr. Paul Bieniasz (right) receives Career Award crystal from Center for Retrovirus Research Director Dr. Patrick L. Green (left).

Dr. Paul Bieniasz during his distinguished research seminar presentation to the Center for Retrovirus Research and OSU faculty, staff, and students.

Dr. Paul Bieniasz during his distinguished research seminar presentation to the Center for Retrovirus Research and OSU faculty, staff, and students.

Dr. Paul Bieniasz during his distinguished research seminar presentation to the Center for Retrovirus Research and OSU faculty, staff, and students.

Dr. Paul Bieniasz during his distinguished research seminar presentation to the Center for Retrovirus Research and OSU faculty, staff, and students.

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