Tiny change in Envelope can make SIV resistant to antibodies

By Andreas von Bubnoff

HIV uses structures that are called Envelope spikes on its surface to enter target cells, a process that’s intercepted by antibodies, molecules the immune system makes to defend against pathogens. This interception of infection by antibodies is called neutralization. Researchers have in recent years found dozens of so-called broadly neutralizing antibodies (bNAbs) in chronically HIV-infected people that can neutralize many, if not most, HIV strains at very low concentrations. Their goal now is to develop a vaccine that can bring the immune system to make such bNAbs.

One challenge is that many HIV variants are much more resistant to antibodies than other, sensitive ones. The reason for this has been unclear—but researchers have now found a tiny change in the Envelope protein that can make simian immunodeficiency virus (SIV), the monkey version of HIV, more resistant to neutralization by some antibodies (Nature 505, 502, 2014).

If this is also true for HIV—and preliminary results suggest it is—it could explain why candidate HIV vaccines have so far shown no or only low efficacy in human trials: they failed to induce antibodies to this resistant form of Envelope. “It probably can explain why RV144 worked a little bit but not a lot,” says Oregon Health & Science University researcher Louis Picker, who was not involved in the study, referring to RV144, the only human trial to date that showed some, albeit low, efficacy of an HIV candidate vaccine of 31.2%.

The new findings come from experiments where the researchers, led by Mario Roederer of the Vaccine Research Center in Bethesda, Md., gave rhesus macaques different types of experimental vaccines that contained certain parts of SIV. Only one of them, a vaccine that contained only the SIV Envelope protein, protected the animals: it reduced the probability of infection after each SIV exposure threefold.

But some of the animals still got infected—even though they had received the vaccine. When the researchers took a closer look at what might have enabled viruses to break through the vaccine protection, they found a tiny change in their Envelope protein: two amino acids (the building blocks of proteins) called alanine (A) and lysine (K) were in certain positions close to one end of the Env protein that are usually occupied by two different amino acids called threonine and arginine.

That’s a small difference, given that the entire Envelope protein is more then 850 amino acids long. But later experiments showed that the difference was enough to make half of these “A/K” viruses resistant to the antibodies in the blood of the vaccinated animals. The researchers calculated that for this to happen, only a tiny fraction—about 2%—of the A/K Envelope proteins must have become resistant to the antibodies, because each virus carries many Env proteins on its surface, and just one of them needs to be antibody resistant to infect a target cell.

Why the different amino acids made only a tiny fraction of Envelope proteins resistant to antibody binding is unclear. But the researchers speculate that they somehow allowed the Envelope to sometimes fold into a different shape, which made it more difficult for antibodies to bind to most parts of it.

To better understand how this works, the researchers now plan to isolate the resistant A/K form of the SIV Envelope protein and study its structure. But the fact that the resistant A/K Envelope form is so rare could make this quite difficult—and is probably the reason why the resistant form has so far escaped the attention of researchers.

Isolating the resistant form would also enable researchers to create structures that mimic it to develop a vaccine that can induce antibodies to resistant virus variants. “If we could purify that form, or figure out how to stabilize it in some way and make it in large quantities, we could immunize with it,” Roederer says.

To be sure, the A/K change doesn’t seem to make all parts of Envelope resistant to antibody binding. One part of Envelope that the virus uses to bind to a target cell protein called CD4 when it enters target cells seems to be unaffected, because the researchers found that antibody-like molecules that resemble CD4 could still bind the resistant A/K form of Envelope.

Therefore, another way to make a vaccine that protects from the resistant A/K viruses is to make sure that the vaccine induces CD4-specific bNAbs, such as one called VRC01. “If we figure out an immunogen that elicits VRC01 in everyone, then we are done,” Roederer says.

That approach, of course, has its own challenges (see VAX May 2013 Primer on Understanding How a Vaccine May be Designed to Induce Broadly Neutralizing Antibodies). Says Roederer: “If it was easy, it would have been done.”