Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope (ENV). The envelope glycoprotein trimer is essential for HIV entry into cells as it plays a vital role in attachment to specific cell surface receptors. To develop a vaccine against HIV, researchers need a detailed map of these glycans to reveal the small holes in the shield where antibodies might penetrate and neutralize the underlying viral machinery.
However, the envelope trimer structure has been elusive as its fragility typically causes it to fall apart before it can be imaged. Now, a study from researchers at The Scripps Research Institute (TSRI) describes the high-resolution structure of the HIV envelope glycoprotein trimer responsible for recognition and infection of host cells. The team state that their study is the first to show this HIV envelope trimer, in its natural or ‘native’ form and include a detailed map of a vulnerable site at the base of the protein, as well as the binding site of an antibody that can neutralize HIV. The study is published in the journal Science.
Previous studies show that ideally, antibodies would be able to target HIV’s Env trimer. This fusion machinery is also a valuable target because its structure is highly conserved, meaning the same vulnerabilities exist in many strains of the virus, and antibodies against these sites could be neutralizing. Unfortunately, a shield of sugar molecules, called glycans, blocks many antibodies from reaching this region. The HIV trimer is also notoriously unstable making it hard for scientists to capture a good image. The current study provides images of the elusive HIV Env trimer structure, including a more-complete structure than ever seen before.
The current study employs cryo-electron microscopy (EM), a 3D imaging technique that enables resolution of atomic-level details. The lab devised a strategy to extract and purify the fragile HIV Env trimer from its membrane environment and load it into the microscope for imaging, a process which involved the use of an HIV broadly neutralizing antibody, PGT151. Results provided the complete fusion machinery, complex glycans and a vaccine target called the membrane proximal external region (MPER). Data findings show that the structures also demonstrated that the trimer is malleable and can subtly alter its shape; this shape-shifting is both part of its fusion machinery and a way to dodge neutralizing antibody responses.
Results show that the structure also includes a highly detailed picture of the PGT151 site of vulnerability, the most complex and extensive broadly neutralizing site that antibodies can recognize, yet described. Data findings show that in addition to targeting several glycans on the surface of Env, PGT151 binds to the fusion peptide, rendering the virus unable to infect host cells.
The team surmise that their findings give the global medical community a better idea of the antibody traits needed to negotiate the glycan shield, an extremely important fact to know when developing a vaccine against HIV. For the future, the researchers state that the newly solved structure is similar to the Env trimer-mimicking structures being developed for an HIV vaccine and confirms that vaccine strategies are on target. They go on to conclude that the global medical community can now build on that work to develop superior vaccine candidates.
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
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Michelle Petersen’s copy was used in the highly successful marketing campaign for the mega-hit film ‘Jumanji: The Next Level, starring Jack Black, Karen Gilian, Kevin Hart and Dwayne ‘The Rock’ Johnson. Michelle Petersen’s copywriting was part of the film’s coverage by the Republic TV network. Republic TV is the most-watched English language TV channel in India since its inception in 2017.
An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.