Scientists jump hurdle in HIV vaccine design

May 26, 2017, The Scripps Research Institute
HIV infecting a human cell. Credit: NIH

Scientists at The Scripps Research Institute (TSRI) have made another important advance in HIV vaccine design. The development was possible thanks to previous studies at TSRI showing the structures of a protein on HIV's surface, called the envelope glycoprotein. The scientists used these structures to design a mimic of the viral protein from a different HIV subtype, subtype C, which is responsible for the majority of infections worldwide.

The new immunogen is now part of a growing library of TSRI-designed immunogens that could one day be combined in a vaccine to combat many strains of HIV.

"All of this research is going toward finding combinations of immunogens to aid in protecting people against HIV infection," said TSRI Professor Ian Wilson, Hanson Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI.

The research, published recently in the journal Immunity, was led by Wilson and TSRI Professor of Immunology Richard Wyatt, who also serves as Director of Viral Immunology for the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at TSRI.

The new study was published alongside a second study in Immunity, led by scientists at the Karolinska Institute in Stockholm, which showed that the developed in the TSRI-led study can elicit neutralizing antibodies in non-human primates.

"Together, the two studies reiterate how structure-based immunogen design can advance vaccine development," said Wyatt.

Solving the Clade C Structure

HIV mutates rapidly, so there are countless strains of HIV circulating around the world. Of these strains, scientists tend to focus on the most common threats, called clades A, B and C.

Like a flu vaccine, an effective HIV vaccine needs to protect against multiple strains, so researchers are designing a set of immunogens that can be given sequentially or as a cocktail to people so their immune systems can prepare for whatever strain they come up against.

In 2013, TSRI scientists, led by Wilson and TSRI Associate Professor Andrew Ward, determined the structure of a clade A envelope glycoprotein, which recognizes host cells and contains the machinery that HIV uses to fuse with cells. Because this is the only antibody target on the surface of HIV, an effective HIV vaccine will have to trigger the body to produce antibodies to neutralize the virus by blocking these activities.

Building on the previous original research, the scientists in the new study set out to solve the structure of the clade C glycoprotein and enable the immune system to fight clade C viruses.

"Clade C is the most common subtype of HIV in sub-Saharan Africa and India," explained study co-first author Javier Guenaga, an IAVI collaborator working at TSRI. "Clade C HIV strains are responsible for the majority of infections worldwide."

The scientists faced a big challenge: the clade C envelope glycoprotein is notoriously unstable, and the molecules are prone to falling apart.

Guenaga needed the molecules to stay together as a trimer so his co-author Fernando Garces could get a clear image of the clade C glycoprotein's trimeric structure. To solve this problem, Guenaga re-engineered the glycoprotein and strengthened the interactions between the molecules. "We reinforced the structure to get the soluble molecule to assemble as it is on the viral surface," Guenaga said.

The project took patience, but it paid off. "Despite all the engineering employed to produce a stable clade C protein, these crystals (of clade C protein) were grown in very challenging conditions at 4 degrees Celsius and it took the diffraction of multiple crystals to generate a complete dataset, as they showed high sensitivity to radiation damage," said Garces. "Altogether, this highlights the tremendous effort made by the team in order to make available the molecular architecture of this very important immunogen."

With these efforts, the glycoprotein could then stay together in solution the same way it remains together on the virus itself. The researchers then captured a high-resolution image of the glycoprotein using a technique called x-ray crystallography.

The researchers finally had a map of the clade C glycoprotein.

Vaccine Candidate Shows Promise

In a companion study, the scientists worked with a team at the Karolinska Institute to test an immunogen based on Guenaga's findings. The immunogen was engineered to appear on the surface of a large molecule called a liposome—creating a sort of viral mimic, like a mugshot of the virus.

This candidate indeed prompted the immune system to produce antibodies that neutralized the corresponding clade C HIV strain when tested in non-human primates.

"That was great to see," said Guenaga. "This study showed that the immunogens we made are not artificial molecules—these are actually relevant for protecting against HIV in the real world."

Explore further: Researchers develop new method to 'fingerprint' HIV

Related Stories

Researchers develop new method to 'fingerprint' HIV

March 28, 2017
HIV is a master of disguise. The virus uses a shield of sugar molecules, called glycans, to hide from the immune system and block antibodies from attacking it.

Scientists discover antibodies that target holes in HIV's defenses

September 12, 2016
A new study from scientists at The Scripps Research Institute (TSRI) shows that "holes" in HIV's defensive sugar shield could be important in designing an HIV vaccine.

Scientists shows AIDS vaccine candidate successfully 'primes' immune system

June 18, 2015
New research led by scientists at The Scripps Research Institute (TSRI), International AIDS Vaccine Initiative (IAVI) and The Rockefeller University shows in mice that an experimental vaccine candidate designed at TSRI can ...

Findings in humans provide encouraging foundation for upcoming AIDS vaccine clinical trial

March 24, 2016
Some people infected with HIV naturally produce antibodies that effectively neutralize many strains of the rapidly mutating virus, and scientists are working to develop a vaccine capable of inducing such "broadly neutralizing" ...

Scientists find surprising trait in anti-HIV antibodies

November 17, 2015
Scientists at The Scripps Research Institute (TSRI) have new weapons in the fight against HIV.

Study makes major advance toward more effective, long-lasting flu vaccine

August 24, 2015
Scientists from The Scripps Research Institute (TSRI) and the Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen) have found a way to induce antibodies to fight a wide range of influenza subtypes—work that could ...

Recommended for you

New simulation tool predicts how well HIV-prophylaxis will work

June 14, 2018
A new mathematical simulation approach predicts the efficacy of pre- and post-exposure prophylaxis (PrEP) medications, which help prevent HIV infection. The framework, presented in PLOS Computational Biology by Sulav Duwal ...

Many at risk for HIV despite lifesaving pill

June 11, 2018
Multiple barriers may stop high-risk individuals from accessing an HIV drug that can reduce the subsequent risk of infection, according to a new University of Michigan study.

Active HIV in large white blood cells may drive cognitive impairment in infected mice

June 7, 2018
Macrophages, large white blood cells that engulf and destroy potential pathogens, harbor active viral reserves that appear to play a key role in impaired learning and memory in mice infected with a rodent version of HIV. ...

HIV vaccine elicits antibodies in animals that neutralize dozens of HIV strains

June 4, 2018
An experimental vaccine regimen based on the structure of a vulnerable site on HIV elicited antibodies in mice, guinea pigs and monkeys that neutralize dozens of HIV strains from around the world. The findings were reported ...

HIV study reveals new group of men at risk of infection

June 4, 2018
A group of men who may be underestimating their HIV risk has been identified in a new study.

Discovery reveals how cells try to control levels of key HIV protein

May 31, 2018
One of the many challenges in treating HIV is that the virus can lie dormant in cells, quietly evading immune detection until it suddenly roars to life without warning and begins replicating furiously. Salk Institute researchers ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Osiris1
not rated yet May 29, 2017
Sad so many had to die before meaningful research advanced to help the rest.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.