Could a previously unknown protein movement be key to an HIV vaccine?

You may know from the COVID-19 pandemic that vaccines target the spike protein on the surface of the SARS-CoV-2 virus. The spike protein latches onto human cells and opens a gate for SARS-CoV-2 to enter the body. To prevent this, vaccines train the immune system to make antibodies that recognize and attack the spike, ideally killing the virus before it invades our cells.

But as the virus circumnavigates the globe, it evolves. Randomly acquired genetic mutations morph the virus into unique variants with altered spike proteins. The more a spike’s “fingerprints” change, the more our vaccinated immune systems fail to recognize the new invaders. That’s why we started needing updated vaccines to retrain the immune system to spot the spikes of the most commonly circulating COVID variants.

Though we don’t yet have a successful HIV vaccine, the process is analogous in many ways. Current vaccine research targets the only protein on HIV’s surface, called the envelope protein, which—like the spike protein—mediates how the virus enters cells. “That’s why it’s so important for targeting, because if you can stop it from fusing, then the virus never gets in the cell in the first place,” says Rory Henderson, Ph.D., a structural biologist at the Duke Human Vaccine Institute.

Henderson and his colleague Ashley Bennett, Ph.D., also from the Duke Human Vaccine Institute, recently published findings that may help vaccine researchers overcome one hurdle for effectively targeting this protein—locking down its movements.

HIV Vaccine Design Is Hard

Though an HIV vaccine might in some ways be analogous to a SARS-CoV-2 vaccine, finding one is a lot more complicated for a variety of reasons. HIV evolves mutations at an immensely higher rate than SARS-CoV-2, so vaccine candidates can’t look for individual signatures like a spike. Instead, an HIV vaccine would need to induce broadly neutralizing antibodies that recognize and attack a wide variety of HIV variants.

A further wrinkle is that these broadly neutralizing antibodies are slow to evolve. The immune systems of people living with HIV do produce antibodies against the virus, but most don’t effectively attack it. Tongqing Zhou, Ph.D.—chief of the structural biology section of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases—describes the process as a kind of arms race between the immune system and HIV. “The police and the bad guy fight each other,” he says.

Over time, as the immune system and virus try to out-evolve one another, antibodies become more effective against HIV, but it’s a random and slow process. Some people’s immune systems can suddenly evolve a mutation that produces a particularly potent broadly neutralizing antibody with a substantial advantage over many HIV variants. But this often takes years after someone has acquired HIV.

“Those are not easy to get,” says Zhou, who was not involved with the Duke research. “They are really rare events in the evolutionary process.” So, for a potential vaccine to work, researchers must develop ways to prod the immune system to manufacture these “improbable mutations” much more quickly.

Distracting Movements

The way the envelope protein moves also complicates things. The goal is to produce broadly neutralizing antibodies that bind to specific sites, called epitopes, on the surface of the envelope protein. But the protein is in nearly constant motion trying to evade the immune system, and when it opens, the immune system becomes distracted.

When the HIV envelope protein unfolds, it reveals other proteins within, which can then access and infect a cell in a process called fusion. In contrast to the rapidly evolving envelope protein on the surface, the internal proteins involved in fusion don’t change much over time. Henderson says they can’t tolerate much genetic variation because what they do is so intricate.

As a result, when the envelope opens, it exposes sites that the immune system is extremely familiar with. It’s as if red flags pop up, saying, “Over here! Attack me!” and the immune system obligingly produces antibodies that flock to these regions. Unfortunately, this does nothing to prevent infection.

“And so, there’s recognition that we needed to stop that movement,” says Henderson. But so far, efforts to stop or stabilize these movements haven’t been fully successful.

A New Movement Discovered

Part of the issue is that HIV’s transition from the closed, pre-fusion state to the open, post-fusion state isn’t binary. “So we know the zero state, we know the one state, but there’s a lot of transition we do not know,” says Zhou.

Imagining the process as an opening flower, researchers know what it looks like fully closed and fully open, but the petals don’t suddenly snap open all at once. Instead, each one may open at different times, at different speeds, and in an unknown sequence.

Henderson, Bennett, and their colleagues used x-ray scattering to investigate rapid, atomic-scale movements in the envelope protein and found something unexpected. “What we found was a movement that nobody knew about, so it hadn’t been stabilized,” says Bennett.

Many previous vaccine studies have produced antibodies that bound to a partially open state, which Bennett says shouldn’t occur if the envelope protein’s movement had been fully locked down. It’s possible that previous research didn’t succeed in accomplishing this because they hadn’t designed a way to prevent this newly discovered movement.

“This study basically pinpointed where that rearrangement was occurring and told us exactly what we needed to do to block [it],” says Henderson.

Though encouraged by the new findings, Zhou says this isn’t likely a eureka moment. “I would not say this is a breakthrough,” he says, “but it [does] actually give us a lot finer understanding of how this transition happens.” That’s important, he adds, because it gives researchers another approach to try to fully lock down the protein’s movements. “This is [a] location that we need to pay attention to, but there might be other locations we’re still not finding yet,” says Zhou.

Bennett acknowledges other transitions likely exist. “There’s probably a whole host of other intermediate states that we haven’t identified yet that are important in this process,” she says, adding that ongoing work will search for those.

Vaccine development is time consuming and iterative, says Bennett. Researchers must identify candidates, test them in the lab, in animals, and finally in humans. If they don’t perform well at any stage, designs have to be tweaked and the process begins anew. Whether a breakthrough or not, Bennett says that she hopes these findings will bring HIV vaccine research one step closer to the finish line. “So that each time we are iterating, [we’re] actually making progress towards that final goal instead of just running around in circles.”

By Andy Carstens