155 research outputs found
A Potent, Long-lasting HIV Capsid Inhibitor
No full textAntiretroviral drugs have saved the lives of millions living with HIV/AIDS. However, problems with drug resistance limit available treatments, and inconsistent adherence to daily dosing schedules can lead to poor outcomes and new infections. Long-acting drugs that can overcome drug resistance by targeting new classes of viral proteins are therefore needed. University of Utah Health researcher Wesley Sundquist, PhD, and colleagues performed mechanistic studies and completed a phase 1 clinical trial of Lenacapavir, a molecule that inhibits the HIV capsid (outer shell). Lenacapavir is long-acting due to its high potency, slow release from the injection site, and slow clearance from the body. Single doses of Lenacapavir injected under the skin maintained antiviral concentrations for more than 6 months. The study validates therapies that target the HIV capsid, and demonstrates the potential of Lenacapavir as a long-acting agent to treat and prevent HIV infections. Lenacapavir was developed by Gilead Sciences, building on studies of HIV capsid structure and function from the Sundquist and Chris Hill, DPhil, laboratories (and others). Following a successful phase 3 trial, Lenacapavir has now been approved for use in Europe, and use in the US is pending FDA approval
Designing Proteins to Carry Cargoes Between Cells
No full textComplex biological processes are often performed by self-organizing nanostructures comprising multiple classes of macromolecules, such as ribosomes (proteins and RNA) or enveloped viruses (proteins, nucleic acids and lipids). Approaches have been developed for designing synthetic self-assembling structures consisting of either nucleic acids or proteins, but strategies for engineering hybrid biological materials are only beginning to emerge. Sundquist, King, Belnap and colleagues reported the de novo design and characterization of proteins that direct their own assembly and release from human cells within membrane vesicles. These virus-inspired delivery systems can also transfer biological cargoes between cells, and therefore represent an important first step in the development of new synthetic systems for delivering therapeutic cargoes into diseased target cells
Cellular Membrane Remodeling
No full textCells are constantly severing, fusing and reshaping their membranes. One of the most important cellular membrane remodeling systems is the ESCRT (Endosomal Sorting Complexes Required for Transport) pathway, whose cellular functions include endosomal membrane remodeling, membrane repair, enveloped virus budding, closure of the nuclear envelope, and cytokinetic abscission. Subunits of the ESCRT-III complex perform key roles in these processes by forming membrane-bound filaments. To understand how these filaments shape membranes, Frost, Sundquist and colleagues used cryo-EM to determine the first high resolution structure of an ESCRT-III filament. The structure showed how ESCRT-III subunits open up and interlock in an elaborate domain-swapped filament architecture, unexpectedly revealed that ESCRT-III filaments contain two ESCRT-III strands, and suggested how analogous ESCRT-III filament architectures can curve and constrict membranes to different degrees and in different directions
A Protein that Blocks Virus Budding
No full textHIV and other enveloped viruses wrap themselves in the cell\u27s external membrane exterior, forming buds. They are then released from cells using membrane-cutting machinery (called the ESCRT pathway) that they "steal" from the cell. This broad dependence upon the ESCRT pathway provides a potential target for blocking the replication of many different viruses. However, cells depend on the ESCRT pathway to; perform critical functions, meaning that ESCRT-blocking strategies can also be toxic for cells. A collaboration between the labs of University of Utah Health researchers Nels Elde, PhD, and Wesley Sundquist, PhD, showed that some mammals contain duplicated and shortened genes for a key ESCRT protein. The resulting "retroCHMP3" proteins block the release of HIV and other enveloped viruses. Remarkably, retroCHMP3 proteins from primates and mice appear to work by delaying ESCRT processes, causing extreme damage to HIV and other viruses but little harm to cells. This discovery creates the possibility of engineering retroCHMP3 mice and testing whether they are broadly protected against enveloped viruses, with the long-term goal of finding new ways to target the ESCRT pathway to counter viral infections
Structures and Mechanisms of Protein Remodeling Machines
No full textWhen a cellular protein has done its job or lost its utility, it should be removed, recycled, or remodeled. These tasks are performed by members of the ubiquitous family of AAA ATPases (ATPases associated with diverse cellular activities) that convert the energy of ATP hydrolysis into mechanical forces that can unfold protein aggregates, degrade unwanted proteins, and remodel protein complexes. To learn how AAA ATPases unfold proteins, Hill, Shen, Sundquist, and colleagues used electron cryomicroscopy to determine structures and elucidate the common mechanisms of several different AAA ATPases in complex with their polypeptide substrates. The team found that each enzyme forms a hexameric ring shaped like a lock washer, with the substrate in the central pore
HIV Drug Development
No full textOur NIH P50 CHEETAH Center supports basic research in HIV structural biology and molecular virology, with the long-term goal of identifying effective new strategies for therapies, vaccines, and cures. Fundamental studies of HIV capsid structure and function performed by Sundquist, Hill, and colleagues formed the basis for Gilead\u27s development of highly potent, and remarkably long-lasting HIV capsid inhibitors that support quarterly dosing. These inhibitors have now entered Phase II clinical trials. Similarly, pioneering studies of D-peptide inhibitors by Kay and colleagues produced a highly potent inhibitor of HIV entry that will enter Phase I trials in 2020
Reconstituting HIV Replication in a Test Tube
No full textReverse transcription and integration are key events in retrovirus replication and are also targets of successful anti-HIV therapies. Reverse transcription creates a double-stranded DNA copy of the viral RNA genome, and integration archives that copy within the genome of the infected cell. However, studies of the mechanisms underlying these steps of the viral life cycle remain challenging because these processes are performed by viral core particles located deep within the infected cell cytoplasm and nucleus. To address this limitation, University of Utah Health investigator Wesley Sundquist, PhD, and colleagues reconstituted efficient HIV reverse transcription and integration in a cell-free system. They showed that the system responds appropriately to antiviral compounds. They also discovered that the viral capsid (the protein shell of a virus) plays an active role in supporting efficient reverse transcription. Thus, the entire core particle, including the outer capsid shell, is the true viral "replication complex". This cell-free system is expected to enable new systematic analyses of viral replication and integration and thus help shed light on the first half of the viral life cycle
Structure of the extracellular domain of matrix protein 2 of influenza A virus in complex with a protective monoclonal antibody
No full textThe extracellular domain of influenza A virus matrix protein 2 (M2e) is conserved and is being evaluated as a quasiuniversal influenza A vaccine candidate. We describe the crystal structure at 1.6 angstrom resolution of M2e in complex with the Fab fragment of an M2e-specific monoclonal antibody that protects against influenza A virus challenge. This antibody binds M2 expressed on the surfaces of cells infected with influenza A virus. Five out of six complementary determining regions interact with M2e, and three highly conserved M2e residues are critical for this interaction. In this complex, M2e adopts a compact U-shaped conformation stabilized in the center by the highly conserved tryptophan residue in M2e. This is the first description of the three-dimensional structure of M2e.
IMPORTANCE: M2e of influenza A is under investigation as a universal influenza A vaccine, but its three-dimensional structure is unknown. We describe the structure of M2e stabilized with an M2e-specific monoclonal antibody that recognizes natural M2. We found that the conserved tryptophan is positioned in the center of the U-shaped structure of M2e and stabilizes its conformation. The structure also explains why previously reported in vivo escape viruses, selected with a similar monoclonal antibody, carried proline residue substitutions at position 10 in M2
W.I Convene a Workshop
Get PDFNewspaper Article - For Conveners & Executive - 'W.I Convene A Workshop'AWI CollectionFor Conveners & Executive •
W. I Convene
The Gray Nun Regional Centre was the
home for approximately fifty members of the
Alberta Women's Institute Executive,
Directors and the Constituency Conveners
from January 20th - 23rd inclusive. The
Workshop was an extensive study of the
factions that will enable our members to do
their best in their communities. Norma
Farquharson, the keynote speaker gave a
seminar on ' Communicating Assertively' to
all those convenors and anyone who joined
for the afternoon. Aileen Kritzinger, an
A. W. I, member, gave an enlightening class
on ' Writing a Resolution'. This also included
the parlimentary procedure in presenting
resolutions. Shirley Myers, Head of Home
Economics Branch, Alberta Agriculture,
A Workshop
/ fit 1
told the ladies of how their department can
always be of assistance in their branch
meetings, handicraft judging and as an
information bureau. ' Effective Speaking' by
Sharon Bazant of St. Albert was a highlight.
It does not matter when we speak, but it
taught us how to always be ready to meet the
challenge. The Provincial Education
Conveners of the A. W. I. presented their goals
and accomplisments in a panel.
These workshops are held once a year for
the executive and conveners, but their
expenses were paid through a grant from the
Wild Rose Foundation this time
Congratulations Echo Hill W.I.
Get PDFNewspaper Article - 'Congratulations Echo Hill W.I.' An Alberta Women's Institute has taken second place in a Canada-wide traffic safety competition.Congratulations
Echo Hill W. I.
An Alberta Women's Institute has taken
second place in a Canada- wide traffic
safety competition, Bill Perkins, farm
safety director for the Alberta Safety
Council announced recently.
The winning group is the Echo Hill
Women's Institute and the prize is the
Carol Lane Award worth ? 500. The annual
contest among Canadian women's
groups is administered by the Canadian
Highway Safety Council through a grant
from the Shell Oil Company, Limited.
The prize winning project of the Echo
Hill group involved mounting red reflective
tape on 396 pieces of district
farm machinery. Echo Hill is the Busby-
Picardville area northwest of Edmonton.
The campaign was undertaken when the
W. I. became concerned over frequent
reports of accidents and near- accidents
involving heavy farm machinery travelling
district roads at night. Fourteen
W. I. members and 11 4- H members attached
the tape to machinery on 73
farms. The material was purchased with
W. I. funds from the Alberta Safety
Council.
On the W. I's safety committee are
Mrs. Lloyd McMillan, Mrs. William Price
and Mrs. Sam Yeomans.
The Carol Lane Awards have been
established, Mr. Perkins said, " to recognize,
foster and reward women's
achievements toward the preservation
of lives through traffic safety pregrams
their community, province or nation."
They are named in honor of the worn-
' s travel director of Shell Oil and are!
given to the three women's groups
which " have developed and directed the"
most effective traffic safety programs
during the previous year."
Other winners for 1959 were the
Toronto Junior League, first prize; and
the Montreal West End Safety Council
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