Less than a year ago, two papers were simultaneously published in Science and Nature. They described, for the very first time, the structure and dynamics of the HIV surface envelope protein, the key tool HIV uses to enter our cells. Within this protein’s structure and movement lies the key to how the virus infects our bodies, as well as an entirely new pathway to an HIV vaccine. The discovery was monumental.
Among the scientists involved in the discovery was Walther Mothes, associate professor of microbial pathogenesis at Yale. Last November, I sat down with Mothes to hear about the study. He explained to me the significance of visualizing this protein, a feat that has ignited new hope for mankind’s defeat of HIV.
“It’s happening,” Mothes said at the end of our interview.
And it is indeed happening. In the past few months, a slew of papers has appeared in Nature, Science, and Cell, building on the structural discoveries made last fall. From achieving successful immunizations in animal models to synthesizing ever more effective vaccine candidates, scientists are advancing HIV research at an unprecedented pace.
Astounded by the rate of scientific progress in this field, I sat down once again with Mothes a few weeks ago to hear about the latest in the quest to conquer HIV, an endeavor that up until recently has been arduous.
The main reason for the slow rate of progress, Mothes explained, is how cleverly HIV evades the human immune system. Last fall, Mothes and his collaborators at Cornell University and the National Institutes of Health at last were able to visualize why HIV has remained so elusive.
The Env protein on the virus’ surface, they discovered, performs a dance that alternates between an open conformation and a closed one. The protein remains in the closed conformation for the majority of its life cycle, opening up only occasionally.
Only when the protein is open is the virus able to attach itself to the CD4 receptor on T cells — a class of cells within our immune system. Once the virus slips into T cells, it can remain undetectable for years. However, by opening up, the virus runs the risk of exposing components that can be attacked by antibodies, molecules secreted by the immune system to recognize and combat pathogens. Antibodies only recognize what the immune system has seen, which in this case is Env’s open conformation. Fortunately for HIV, by the time the antibodies are made and circulated throughout the bloodstream, the now closed Env protein has long retreated into hiding, masking its recognizable components with a thick coat of sugars.
“However,” Mothes said, “in about 10 percent of patients, over many years, the immune system learns to recognize this closed conformation.” This recognition comes in the form of a class of very powerful proteins called broadly neutralizing antibodies. These antibodies often have extended, elongated chains that reach into Env’s closed conformation and recognize the vulnerable components at the core of the protein. After years of hide and seek between the virus and the immune system, the antibodies that the immune system has left are the ones that recognize many different variations of the virus. Hence the title “broadly neutralizing.”
As it turns out, these antibodies are not only the secret behind defending the body against HIV. They are also the key to preparing the body against it: that is to say, an HIV vaccine.
“If you want to make a vaccine, you have to present the closed conformation to the immune system to make these broadly neutralizing antibodies,” Mothes said.
An ideal vaccine would introduce a fixed, closed, non-pathogenic conformation of Env to the bloodstream of a person who is not infected, giving the immune system sufficient time to develop broadly neutralizing antibodies against the closed protein. These antibodies would then be widely accessible in the case of an HIV infection, enabling people to fight off the virus before it ever sees the inside of a human cell.
Since last year’s discovery of Env’s structure and dynamics, a number of research groups have quickly jumped onto vaccine development efforts. These initiatives focus on a strategy called HIV mutant-tracing. The logic goes something like this: Patients who eventually develop broadly neutralizing antibodies were exposed to a certain set of HIV variants in a certain order. If we replicate the Env protein variations in the same sequence as in these patients, we could guide the immune system along a series of steps to produce these extensively potent antibodies.
Research groups have been tracing HIV patients from the beginning to the end of infection, collecting viral genomic sequences and antibody identities at successive time points. “If you know how these patients make the [broadly neutralizing] antibodies, you know how to make the vaccine,” Mothes said.
Ideally, Mothes added, vaccine developers will be able to group all of the viral variations into just three fixed conformations, each of which encompasses many different mutations. “A virus has hundreds of steps. The art is to reduce it to a reasonable number,” he said. The three vaccines would then be administered in three stages, allowing time for the immune system to develop antibodies at each stage.
Using the closed conformation, researchers have already seen promising signs in rabbit immunizations. John Moore and his colleagues at Cornell introduced the closed HIV Env scaffold as a vaccine into rabbits, and the rabbits indeed began producing neutralizing antibodies against the closed conformation.
In parallel, two groups at the Scripps Research Institute and Rockefeller University immunized mice that already expressed antibodies against the first stage, and to their excitement, the mice went on to produce antibodies against the second stage conformation. Their research has confirmed that the mutant-tracing strategy does indeed coax the immune system to produce the powerful broadly neutralizing antibodies required to recognize the closed HIV Env protein.
“It is a proof of concept,” Mothes said.
The production of neutralizing antibodies that Moore’s group saw in rabbits was disappointingly absent when the team tested this vaccine strategy on monkeys. Mothes believes the reason is that monkeys express a T cell CD4 receptor variant that HIV can bind to, while rabbits lack this CD4 variant. The Env conformations used by Moore’s lab are not yet stabilized to the point that they are resistant against opening up for CD4 binding. This is where Mothes comes in.
The synthesis of a new, highly stable, fixed conformation that does not open in response to CD4 was achieved by Peter Kwong’s group at the NIH, with critical contributions by Mothes’ research team just a few weeks ago. The results, describing the biochemical and biophysical aspects of the new structure, were published this June in the journal Nature Structural and Molecular Biology. The conformation contains a disulfide bridge — two sulfur atoms bonded to each other in a strong interaction — as a key stabilizing mutation. The next step is to use this CD4-resistant conformation in immunization studies similar to the ones conducted by the Moore lab.
“It’s the first fixed trimer,” Mothes said, “but not the best. There are going to be more that are going to be better than this one.”
Other groups are already identifying additional modifications to the Env protein that result in significantly elevated stability. “These will be the best scaffolds for vaccines,” Mothes said.
Biomedical research often comes at a high price, and it is not a price to be taken lightly. Every cure for disease depends on knowledge of a diseased state, knowledge that can only be supplied by people who suffer daily the consequences of such debilitating maladies as HIV. And while this knowledge is absolutely essential for scientific progress, it is the suffering of these patients itself that fuels such progress and continuously nurtures our hope for a future devoid of human misery in the claws of disease.
“After years of figuring out what happens in a patient,” Mothes said, “the beauty is that now we are trying to do the same with a patient who hasn’t been infected or suffered from AIDS. Mankind is doing it.”
This article is a development on a previous piece published in the Yale Scientific Magazine.
Kevin Wang is a junior in Ezra Stiles College. Contact him at email@example.com.
(Featured image courtesy of Jonathan Stuckey and Peter Kwong, Vaccine Research Center, NIAID, NIH.)