Paul Bieniasz graduated from the University of Bath, UK in 1990, and began his career
in retrovirology with Jonathan Weber and Myra McClure at St. Mary’s Hospital Medical
School in London. Initially, he worked HIV-1 entry, and the early development of PCR-based
assays to quantify HIV-1 burden in patients 1]. For his Doctoral degree, Bieniasz shifted his focus and worked with McClure on the
foamy viruses. In particular, he characterized novel foamy virus isolates from apes,
in so doing demonstrating a close relationship between ‘human’ and chimpanzee viruses
2]. He also developed some of the first foamy virus-based gene transfer vectors 3] and showed that foamy virus infection was dependent on cell division 4].
After graduating, Bieniasz joined Bryan Cullen at Duke University as a postdoctoral
fellow, from 1996 to 1999, and returned to HIV-1 research. For his first set of experiments,
he exploited sequence differences between the newly identified human and mouse CCR5
proteins to determine sites that were key for strain-dependent interactions with the
HIV-1 envelope 5]. In a second set of studies he again used functional differences between human and
proteins to show that a single amino-acid difference in the cyclin T1 underlay the
differential ability of Tat:P-TEFb complexes to bind TAR and, thus, the species-dependent
activity of HIV-1 Tat 6]. Bieniasz and Cullen also made a key finding that artificial P-TEFb recruitment to
a promoter proximal RNA element was sufficient to stimulate that transcriptional elongation
activity in the absence of Tat 7].
Bieniasz started his own lab at the Aaron Diamond AIDS Research Center and Rockefeller
University in late 1999. Since then he has worked on many and varied aspects of retrovirus
replication. Initially, building on work that he began with Cullen, Bieniasz found
that rodent cells engineered to express human CD4, CCR5 and cyclinT1, could support
early but not late steps in HIV-I replication 8]. His characterization of these novel host range restrictions sparked a long-standing
interest in HIV-1 assembly and budding. Indeed, among the Bieniasz lab’s early findings
was the demonstration that the matrix domain of Gag exerted an auto-inhibitory effect
on Gag-membrane interactions that contributed to the apparent block to HIV-I assembly
in rodent cells 9], 10].
A key set of studies from the Bieniasz lab helped to elucidate the mechanisms by which
so-called ‘late-budding’ domains enable enveloped virus particle release. Specifically,
Bieniasz and colleagues contributed to the discoveries of key roles for Tsg101, ALIX
and HECT-ubiquitin ligases and ubiquitin in the budding of HIV-1, Ebola and other
viruses 11]–14]. These proteins interacted with numerous components of the then newly discovered
ESCRT pathway which the Bieniasz lab showed were important for retrovirus particle
release 12], 15], 16].
For a time, the subcellular location at which HIV-1 particle assembly occurs was controversial.
The Bieniasz lab resolved this question, demonstrating clearly that it occurs at the
plasma membrane 17]. Building on that work, Bieniasz collaborated with Sanford Simon to develop imaging
techniques that, for the first time, allowed the genesis of individual virus particles
to be visualized in living cells 18]. This advance enabled unprecedented studies of the dynamics of the assembly and budding
of individual HIV-1 virions. In particular, elaborations of this technique allowed
Bieniasz and Simon to visualize and quantify the dynamics of viral genomic RNA movement
and encapsidation 19], as well as the recruitment of ESCRT proteins to sites of virion release 20].
More recently, the Bieniasz lab developed new biochemical and crosslinking-nextgen
sequencing approaches to reveal, in unprecedented detail, how viral proteins and RNA
interact during particle assembly 21], 22]. This new work has redefined the rules that govern how HIV-1 packages its genome,
and suggests that the unusual A-rich nucleotide composition of the HIV-1 genome helps
to drive viral RNA interaction with Gag molecules as they assemble into virions 22]. These new approaches have also uncovered a striking and specific interaction between
the HIV-1 matrix domain and tRNA, specifically in the infected cell cytoplasm, that
may contribute to the ability of HIV-I matrix to auto inhibit, and thereby delay,
HIV-1 virion assembly 22], 23].
A second major area of interest for Bieniasz has been the discovery and characterization
of intrinsic and innate cellular antiviral defenses. A significant part of this work
has been done with his wife and colleague, Theodora Hatziioannou. The Bieniasz lab’s
first work in this area revealed that primate cells possessed an antiviral activity
that could block HIV-I infection at a post entry step, targeting the incoming viral
capsid 24]. Notably, the specificity of this novel antiviral activity varied dramatically in
a species-dependent manner and could inhibit very diverse retroviruses 25], 26]. The protein responsible for this activity was later identified (by the Sodroski
lab) as TRIM5, and the Bieniasz lab performed key studies of its activity against
diverse retroviruses 27], mapped determinants of specificity in the viral capsid and in TRIM5 28], 29], and provided insights into TRIM5’s mechanism of action 30], 31].
Bieniasz’s interests in HIV-1 assembly and in antiviral proteins have sometimes overlapped.
For example, his group showed that RNA recruited APOBEC3 into virons through apparently
sequence-nonspecific interactions 32]. A seminal contribution by the Bieniasz lab was a collection of studies on the HIV-I
Vpu protein. Initially, they showed that Vpu antagonized the action of an unknown
interferon-induced protein that could apparently tether divergent enveloped viruses
at the surface of infected cells 33], 34]. These studies led directly to the discovery of Tetherin 35], and a series of papers on Tetherin function. For instance, The Bieniasz lab showed
that Tetherin could inhibit the release of remarkably diverse viruses 36] and generated a Tetherin knockout mouse to demonstrate the antiviral action of Tetherin
in vivo 37]. Bieniasz’s group also delineated the molecular mechanism by which Tetherin inhibits
particle release, demonstrating that Tetherin inserted itself into the lipid envelope
of virions to cause their entrapment, and that its overall protein structure and not
primary sequence are required for activity 38], 39]. In other studies with Hatziioannou, Bieniasz showed that SIVs lacking a Vpu protein
often employ another viral accessory protein, Nef, as a Tetherin antagonist 40], 41]. Bieniasz and colleagues found that both of these viral antagonists work in a host
species restricted manner 40], 42], as governed by Tetherin sequence variation They also revealed key aspects of the
molecular mechanisms by which these viral antagonists function 43], 44].
The finding that an interferon-induced protein could directly inhibit HIV-1 replication
inspired Bieniasz to search, in collaboration with his colleague Charles Rice, for
additional interferon induced genes (ISGs) that might contribute to the antiretroviral
activity of interferons 45], 46]. One result of this search was the co-discovery that Mx2 exhibits anti-HIV-1 activity
during the post entry/preintegration steps of HIV-1 replication 47]. The Bieniasz group also showed that Mx2 apparently blocks capsid-dependent entry
of HIV-1 preintegration complexes into the nucleus, and exhibits signatures of diversifying
selection in it N-terminal domain that governs nuclear pore localization and antiviral
activity and specificity 47], 48].
By exploiting knowledge of specific host-range restrictions imposed by antiviral proteins,
Bieniasz, Hatziioannou and their collaborators, Jeff Lifson and Vineet KewalRamani
have engineered HIV-1 to overcome barriers to HIV-1 replication in monkeys 49], allowing the generation of new animal models of HIV-I infection 50]. In particular, Bieniasz and Hatziioannou identified a second example of a TRIM5-CypA
fusion protein in pig-tailed macaques that, remarkably, could not inhibit HIV-1 infection
51]. This discovery enabled the use of viral engineering and adaptation to develop an
HIV-1 strain that, for the first time, can cause AIDS in a non-hominid species 52]. This team has also devised a procedure for generating pathogenic SHIVs that promises
to expand the range of challenge viruses available for HIV-I vaccine studies 53].
In addition to these core interests, Bieniasz has a broad interest in the function
and evolution of a range of viral and host proteins that are involved in retrovirus
replication 54]–58]. The Bieniasz group has also pioneered the field of paleovirology. His group showed
that an extinct retrovirus (HERV-K) could be resurrected in functional form from molecular
fossils that are present in modern genomes 59] and uncovered evidence of ancient interactions between APOBEC3 proteins and retroviruses
in the form of hypermutated endogenous proviruses in humans and chimpanzees 60], 61]. They also completed the first identification of an entry receptor for a presumptively
extinct virus (CERV-2) using a reconstituted ancestral envelope protein 62].
Bieniasz has served on several review and advisory board including the NIH AIDS Molecular
and Cellular Biology study section (2004–2009) including as Chair (2007–2009) and
on the NCI Board of Scientific Counselors (2010–2014). He has been an investigator
of the Howard Hughes Medical Institute since 2008. 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. He was elected
to the American Academy of Microbiology and received an NIH MERIT award in 2011, and
was awarded the Ohio State University Center for Retrovirus Research Distinguished
Career award in 2015.