A less torturous path for antibodies?

A major impediment in trying to develop vaccine candidates that can induce potent and broadly neutralizing antibodies is time. While all antibodies mature to some degree, the bNAbs uncovered from HIV-infected individuals in the chronic stages of disease take much longer to develop and follow much more convoluted developmental pathways. It takes several years of continuous stimulation by the infecting virus to drive mutations or changes in the bNAbs so that they can bind tightly to their targets, a process scientists refer to as affinity maturation  (see VAX Jan. 2011 Primer on Understanding Advances in the Search for Antibodies against HIV). These bNAbs also typically have a long heavy chain complementary determining region 3 (HCDR3) that allow the antibodies to bind more strongly and to target more epitopes on the surface of HIV.

Researchers still do not know if all of these mutations are necessary for these antibodies to neutralize many different strains of HIV, though in some cases studies have shown that reversing most of the mutations resulted in an antibody that could not neutralize HIV, suggesting at least some of the mutations are required.

But Vanderbilt scientist James Crowe suggests that because antibodies with long HCDR3s are found in all healthy individuals, regardless of HIV status, it could be that these long HCDR3s may not be generated through the long affinity maturation but in fact may form much sooner when B cells first encode an antibody.  If so, says Crowe, it may be possible avoid the lengthy detours that bNAbs take to reach adulthood by designing immunogens that more efficiently induce HIV bNAbs with long HCDR3s. Crowe described ongoing research that his lab and others have been doing in the development of high affinity antibodies during a symposium on the final day of the AIDS Vaccine 2012 Conference in Boston, which ran from Sept. 9-12.

Crowe said it is known that antibodies with long HCDR3s exist in humans and mice. What is not known is how frequently these antibodies are able to avoid the autoreactive properties that often compel B cells to eliminate such proteins before they have a chance to reach the peripheral blood. So Crowe’s lab isolated B cells from four healthy HIV-uninfected individuals and examined millions of antibody sequences from three different subsets of B cells, including naïve B cells. They found that the naïve B cell population had a high higher percentage of long HCDR3s than the other B cell subsets, including a higher percentage of very long HCDR3s, which suggested that the somatic mutations that fuel the process of affinity maturation in bNAbs have little effect onHCDR3s.

By threading healthy donor sequences from the large repertoire of B cells to the backbone of the bNAb PG9—which was isolated from an HIV-infected African donor and is considered far less mutated than other bNAb—researchers were also able to generate antibodies with computation and statistical software that were remarkably similar in structure to the potent but relatively unmutated PG9.