Novel epitope for binding of HIV antibodies has major drug delivery implications

Mark Connors

The discovery of a new HIV antibody by researchers at the U.S. National Institutes of Health highlights the need to create vaccines with trimeric delivery systems that resemble those found naturally, said Mark Connors, the team's principal investigator and chief of the HIV-Specific Immunity Section of the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases.

The 35O22 antibody only binds to a specific trimer. "In other words it will only bind to the spike on the virus in its native form. It won't bind to the little pieces of the surface glycoproteins," Connors said in an interview.

He explained that "a trimer is a combination of three proteins, in this case it's three identical proteins. But really each of those three has two subunits, so it's 6 subunits of an HIV envelope that come together to make a trimer. And one of those trimers is what's referred to as the 'viral spike.'"

More details are available in the journal Nature.

The novel epitope is on the viral spike. An epitope is the part of the virus that the immune system recognizes and binds to, enabling drug delivery to commence, in the case of manmade treatments, like a monoclonal antibody or vaccine for HIV.   

The discovery of the novel antibody's epitope means that "if you're going to try and elicit this type of antibody, you're going to need vaccination methods that present the immune the system with something that's close to the native viral spike, with something that's as close to how HIV presents the viral spike surface glycoprotein in nature as possible," Connors said. 

In a future therapy, the novel antibody would be delivered either subcutaneously or through an intravenous route, Connors said. In addition, he said that because the antibody is very potent, "it might in theory be given less frequently, but we won't know that until it has been given experimentally to animals."

Two other recently discovered HIV antibodies also bind to trimers, he said. Connors stressed that "from a drug delivery standpoint the vaccine that would elicit these antibodies is going to have a trimeric structure." Focusing on keeping the HIV virus's trimers intact is not a common practice, he said: "For many if not most prior vaccination strategies, they're using pieces of that viral spike." This approach would fail to elicit the antibody, rendering it useless against HIV.

Instead, "biochemists must continue to formulate structures that are stable and mimic the viral spike as closely possible," he said. The problem is that in its native form the trimer is very unstable and can dissociate. "What biochemists are trying to do is stabilize the structure." 

Much of the research was carried out at the NIH laboratories in Bethesda. Connors said the antibody is available for licensing from the government by private companies. 

- read the NIH notice
- here's the study abstract