TSRI Scientists Capture First High Resolution Image of Key HIV Protein Transitional State LA JOLLA, CA July 12, 2017 A new, three-dimensional snapshot of HIV demonstrates the radical structural transformations that enable the virus to recognize and infect host cells, according to a new study led by scientists at The Scripps Research Institute (TSRI).
The atomic-scale close-up image reveals an intricate dance between different parts of a key HIV protein complex, known as the envelope (Env) trimer, that takes place just moments before the virus would normally fuse itself to an immune cell's plasma membrane.
One could consider this a missing link' between HIV's previously known prefusion and the post-fusion states, said Andrew Ward, an associate professor at TSRI who led the study.
The image also gives scientists their clearest glimpse yet at the plastic nature of Env, which constantly shifts between different configurations before latching on to human cells.
Several other studies have shown evidence of trimer breathing,' and here we are able to capture two different conformational states of Env at high resolution, said study co-first author Gabriel Ozorowski, a senior research associate at TSRI.
Findings from the study, published online on July 12 in the journal Nature, could provide new potential targets for HIV vaccine designs.
By understanding the molecular details of this fusion intermediate state, we can infer how the trimer transitions between states and engineer mutations or molecules to block those transitions, Ward said.
An Elusive Target
HIV, the human immunodeficiency virus, currently infects about 37 million people worldwide. The development of a vaccine that can prevent as opposed to just manage HIV infections has been largely stymied by the complex and elusive structure of Env.
HIV's Env is a protein complex made up of three identical, mushroom-shaped structures that each contain a stalk-like subunit, gp41, and a cap-like region called gp120. The structures are only loosely connected to one another, enabling the trimer to change shape and making it notoriously difficult to study and target with drugs. In addition, the trimer also frequently mutates its outermost variable loop regions to evade immune attack, and its surfaces are coated with complex sugar molecules (called glycans) that obscure potential drug-binding sites.
But by capturing Env in a configuration that exposes previously unknown patches on the trimer's surfaces, the snapshot presents interesting new prospects for drug developers.
If we can target the newly found pockets with small molecules, then there is the potential to create new fusion inhibitor drugs, Ward said.
Help from a Substitute
The team's ultra-detailed image of Env is actually a composite picture digitally stitched together from thousands of images taken with a cryo-electron microscope.
For HIV infection to occur, Env must first bind with two proteins on an immune T cell's outer surface, a membrane receptor known as CD4, and then to a coreceptor, either CXCR4 or CCR5. For the new study, the scientists created a protein that included a modified form of Env genetically engineered for stability that is bound to CD4 and 17b, a human antibody that resembles CXCR4/CCR5 and is used as a stand-in for the coreceptors. The trimer complexes are then embedded into a thin layer of ice and placed under the microscope for imaging.
The electron beam is scattered by the protein atoms, leading to detailed two-dimensional images, said study co-first author Jesper Pallesen, also a senior research associate at TSRI. We take about 2,000 images, each one containing thousands of complexes frozen in random orientations, and we computationally align them to create a high-resolution, three-dimensional snapshot.
A New State
The new snapshot of Env in its fusion intermediate state reveals that upon binding to CD4, the V1 and V2 variable loops of gp120 flip away from the center of the trimer, exposing the coreceptor binding site. CD4 binding also triggers parts of the gp41 stalk to rearrange themselves to create a small pocket of space inside the trimer. This pocket acts to stabilize the fusion peptide an amino acid sequence that anchors itself in the host cell as it moves from the base of the trimer toward the interior in preparation for membrane fusion.
Due to its critical role in infection, the fusion peptide region of HIV is particularly resistant to mutation and thus a sought-after drug target. If you can target this particular stretch of amino acids, then the virus has a hard time escaping, Pallesen said.
However, actually hitting this target has proven difficult because the fusion peptide rarely stays still. Prior to CD4 binding, the fusion peptide is floating and flopping around outside of the trimer, Ozorowski said. What we see for the first time in our structure is that when Env binds CD4, the fusion peptide moves closer to the trimer's interior and adopts a more stable state as it prepares to anchor into the host cell's membrane.
Breathing
The team also conducted a second antibody-substitute experiment to obtain the clearest picture yet of Env's shapeshifting abilities. Because Env is a metastable fusion machine, it has been long understood that it must be a malleable structure, Ward said.
Swapping out CD4 for a similarly shaped antibody, b12, the team was able to show that in addition to a closed state, in which the CD4 binding site is hidden, and an open state that is ready for CD4 binding, Env also contorts into a partially open configuration that accommodates b12 but not CD4.
For infection to happen, the trimer must transition from a closed state to an open state that brings the fusion peptide in close proximity to the host cell, Ozorowski said. Sampling vario
Most recent headlines
04/08/2024
Dalet, a leading technology and service provider for media-rich organizations, is excited to announce Santiago Solanas as its new Chief Executive Officer (CEO)....
03/06/2024
Dalet, a leading technology and service provider for media-rich organizations, a...
28/04/2024
Mediahaus delivers the first SRT live-streaming sports production over 5G with U...
27/04/2024
On April 26, L3Harris Chair and CEO Christopher E. Kubasik joined CNBC's Mor...
27/04/2024
PORTLAND, Oregon Audinate Group Limited, the developer of the Dante AV-over-IP solution, announced significant new additions to Dante Connect, its cloud-based D...
27/04/2024
TORONTO Bell Media has launched 10 English and French-language FAST channels featuring entertainment, factual, news, and sports programming. The new free stream...
27/04/2024
An extensive new analysis of the news segments in the broadcast evening news programs of ABC, CBS, NBC and PBS has found that broadcasters devoted most of their...
27/04/2024
GERMANTOWN, Md. EchoStar's Hughes Network Systems has opened a new manufacturing facility and private 5G incubation center in Germantown, Maryland....
27/04/2024
Harry Pappas, one of three brothers who founded Pappas Telecasting Companies in 1971, died April 24. He was 78 years old....
27/04/2024
ATLANTA and LONDON Mexican telecommunications and broadcast company Televisa has selected Synamedia for an overhaul of its broadcast distribution....
27/04/2024
Participate in the Survey - The Impact of AI on Media and the Creative Industry
Pascal Wagner April 26, 2024
0 Comments
By participating in this surve...
27/04/2024
SDVI Rally Access Workstation Earns Two Top Awards at 2024 NAB Show
Brie Clayton April 26, 2024
0 Comments
SDVI, the leading platform provider for clo...
27/04/2024
Berklee's Music and Health Institute Launches Community Health Musician Cert...
27/04/2024
Charter Communications reported higher first-quarter profits despite continued cord-cutting and competition for broadband customers....
27/04/2024
Two environmentally-focused groups are partnering to engage the unscripted TV world in finding better ways to address climate change. Reality of Change is an ec...
27/04/2024
Sarah Garcia has been promoted to weekend anchor at KTLM McAllen, Texas, known as Telemundo 40. Starting April 27, she will anchor Noticias Telemundo 40 weekend...
27/04/2024
CBS Sports said it launched a new 24-hour free, ad supported streaming television (FAST) channel devoted to the UEFA Champions League....
27/04/2024
Comcast chairman and CEO Brian Roberts received $35.4 million in compensation in 2023, up 11% from the previous year, according to a proxy statement filed by th...
27/04/2024
Art Happens Here With John Lithgow, which sees the actor study dance, ceramics, silk-screen printing and vocal jazz with students in Los Angeles, debuts on PBS ...
27/04/2024
Remember Leave It to Beaver? Bewitched? Dragnet? When cable ratings were rising?...
27/04/2024
Next up for the weekend binge at Catchy Comedy is Gomer Pyle, U.S.M.C. Every weekend, Catchy Comedy features The Catchy Binge, a marathon of a classic sitcom....
26/04/2024
Sundance Film Festival CDMX 2024 kicks-off today with screenings in 5 theaters in Mexico City and the opening-night film, FRIDA, directed by Carla Guti rrez...
26/04/2024
[Editor's Note: This interview is part of a larger feature about the women d...
26/04/2024
Once again this year, SGL Carbon opened its doors to interested children and young people. On the occasion of the German Girls and Boys Day, which took place on...
26/04/2024
Orders1 of $5.5 billion; book-to-bill of 1.06x
Revenue of $5.2 billion, up 17%,...
26/04/2024
Five Considerations For Communications Modernization In The 21st Century
In the digital-enabled battlespace, the Joint Force needs to shoot, move and communica...
26/04/2024
CBS Sports has launched Champions League as a new, 24-hour streaming channel that will serve as the year-round destination for nonstop highlights of the UEFA ...
26/04/2024
Despite tough competition in the streaming space, Roku reported solid results in Q1 2024, beating revenue expectations, with total net revenue up 19% YoY to $88...
26/04/2024
LONDON AND TORONTO Pinewood Toronto Studios has appointed Sarah Farrell as general manager of the Studios in downtown Toronto....
26/04/2024
Quantum to Offer Advanced Filesharing Technology and Performance in StorNext and...
26/04/2024
FilmLight Colour Awards welcomes 2024 entries and introduces new Emerging Talen...
26/04/2024
Picture Shop Announces Chris Evans as Head of Unscripted
Brie Clayton April 26, 2024
0 Comments
Picture Shop announced Chris Evans will lead Unscripte...
26/04/2024
Participate in a Survey - The Impact of AI on Media and the Creative Industry
Pascal Wagner April 26, 2024
0 Comments
By participating in this survey,...
26/04/2024
Toy maker Mattel said it is working with Samsung to launch its first free ad-supported streaming television (FAST) channels later this year....
26/04/2024
Trusted Media Brands (TMB) said it named Marty Moe as president....
26/04/2024
Ron Howard is the director on Jim Henson Idea Man, a documentary that premieres on Disney Plus May 31. Henson of course created Kermit the Frog, Miss Piggy, Big...
26/04/2024
The ice continues to melt under the regional sports network business as the Seattle Kraken of the National Hockey League have made a long-term deal to broadcast...
26/04/2024
Heading into the upfronts, Warner Bros. Discovery said it launched Olli, a first-party data platform advertiser can use for converged, targeted advertising camp...
26/04/2024
CBS has renewed the drama The Equalizer, which will see season five on in 2024-2025. Queen Latifah stars....
26/04/2024
The CW has entered into an exclusive multiyear broadcast partnership for the Miss USA Pageant and the Miss Teen USA Pageant. The 73rd Miss USA Pageant will air ...
26/04/2024
Fuse Media isn't mincing words in a campaign urging its young viewers to register and participate in the 2024 elections....
26/04/2024
Dead Boy Detectives, a series from Neil Gaiman about a detective agency staffed by ghosts, debuts on Netflix April 25. George Rexstrew and Jayden Revri are in t...
26/04/2024
The Story Collective has gradually repurposed the former Mortlake Brewery to include production offices, workshops and sound stages
By Matthew Corrigan
Publi...
26/04/2024
Perkett joins the company following a 25 year career in product management, product marketing, engineering and user experience (UX) across multiple industries
...
26/04/2024
Teradek, the industry leader in wireless video transmitters and receivers, announced today the launch of new Bolt 6 LT 750 and Bolt 6 Monitor Module 750 RX with...
26/04/2024
NEW YORK Amagi has appointed Richard Perkett chief product officer (CPO)....
26/04/2024
WASHINGTON, D.C. The National Association of Broadcasters (NAB) has announced the results of the 2024 NAB Radio and Television Board of Directors elections. The...
26/04/2024
EL SEGUNDO, Calif. & NEW YORK Mattel has announced a deal to launch its first three 24/7 free ad supported streaming (FAST) channels on Samsung TV Plus, Samsung...
26/04/2024
PORTLAND, Maine Viewers here can now receive the NextGen TV signals of five local stations with the launch of ATSC 3.0 service from host station WPFO, which is ...
TSRI Scientists Capture First High Resolution Image of Key HIV Protein Transitional State LA JOLLA, CA July 12, 2017 A new, three-dimensional snapshot of HIV demonstrates the radical structural transformations that enable the virus to recognize and infect host cells, according to a new study led by scientists at The Scripps Research Institute (TSRI).
