Development of broadly neutralizing antibodies against HIV: It's complicated

Researchers have lately found dozens of broadly neutralizing antibodies (bNAbs) in HIV-infected people. Unlike their less capable peers, these relatively rare antibodies can neutralize most circulating HIV strains. But only about 20% of HIV-infected people develop bNAbs. What’s more, compared with their precursors in the germline, bNAbs accumulate a large number of mutations, or unusual structural features, to acquire their impressive breadth and potency—through a process known as affinity maturation that appears, in most cases, to take many years. 

Researchers are keenly interested in tracking their development in the hope of using that information to devise vaccines that elicit bNAbs in people. As part of that effort, they are also investigating what HIV variants are present over time to induce bNAbs and their precursors. This information, they hope, will allow them to develop immunogens that induce the precursors of bNAbs and accelerate the process by which they ordinarily mature. But recent studies reveal that there are still many gaps in our understanding of how bNAbs develop.

Last year, Penny Moore of the National Institute for Communicable Diseases in Johannesburg, South Africa, and her colleagues described the HIV variants in people who eventually develop a bNAb similar to PGT128 (Nat. Med. 18, 1688, 2012). This potent bNAb targets a sugar residue connected to an amino acid at position 332, at the base of the so-called V3 loop of HIV’s envelope protein, or Env. 

Some of the people with PGT128-like bNAbs in Moore’s study were initially infected with an HIV variant that had the sugar at position 332. But, to their surprise, the researchers also found that two patients who eventually developed PGT128-like antibodies were initially infected with an HIV variant that lacked the sugar at this position. Instead, the virus carried the sugar at position 334, and only developed an escape mutation that involved switching the sugar to position 332 six months later. Once at position 332, the sugar induced a new wave of antibodies that eventually gave rise to the PGT128-like bNAbs that were later observed. 

But the mere presence of a sugar residue at position 332 of HIV Env may not always suffice for the development of PGT128-like bNAbs, according to a recent study led by Cynthia Derdeyn of the Emory Vaccine Center at Emory University. They report that in a patient who was initially infected with an HIV variant that had the sugar at position 332, the virus developed an escape mutation five months after infection that involved switching the sugar from position 332 to 334. Eventually, the patient developed a bNAb response that was different from PGT128 (PLoS Pathog. 2013, doi:10.1371/journal.ppat.1003173). 

This shows, Derdeyn says, that the mere presence of a sugar residue at position 332 doesn’t always pave the way towards the development of a PGT128-like bNAb response. Timing and context also play a role. “In our case, probably, the B cells were driven away from the [332 sugar] as opposed to being focused on it,” she says. “You can’t just put in a [sugar] and get breadth. We think it’s the timing and sequence of events that are going to determine that. It’s much more of probably what [the B cells] see first and and what they see next.” 

To Moore, Derdeyn’s findings illustrate that we still don’t know all of the factors that lead to the induction of bNAbs. “It does highlight that even when somebody is infected with a virus that contains all the broadly neutralizing antibody epitopes, that in no way guarantees that they will develop antibodies to [those epitopes],” she says. “So there are huge black boxes in our understanding of how these antibodies develop.”