HIV Broadly Neutralized by Single Family of Antibodies

Findings of study provide new options for future vaccine development.

A single family of antibodies was found to broadly neutralize different strains of HIV, according to the results of a recent study.

The study, published in the September 25, 2014 issue of the journal Cell, examines the evolution of the antibodies into diverse structures that attack a vulnerable site on the virus. The results of the study may offer significant clues in the development of a future HIV vaccine, the study noted.

"In a sense, this antibody family takes more than one shot on goal in order to hit divergent forms of HIV," said Ian A. Wilson, member of the Skaggs Institute for Chemical Biology at the Scripps Research Institute.

The research is part of ongoing efforts to "retro design" an HIV vaccine, based on the study of rare, natural antibodies that effectively hit the most vulnerable sites on the virus.

Traditional vaccine designs include weakened or inactivated virus particles or large viral subunits in an attempt to generate long-term immune protection. This approach is thwarted by HIV, which protects vulnerable sites with a surface envelope protein that mutates rapidly across different strains, coating the surface with glycans that are difficult for antibodies to grip, the study noted.

The immune system can eventually penetrate the glycan shield in some HIV patients, however, by producing antibodies that can grab or block sites on the virus that don't experience significant change across strains because of their involvement in crucial functions such as docking or fusing with host cells.

These antibodies are rare, however, and are not usually produced in high enough numbers to help patients already infected with the virus. Researchers noted a previous study where the infusion of the PGT121 antibody was able to protect monkeys from new infections with simian HIV and significantly lowered viral levels in monkeys that were already infected.

The main challenge for researchers is taking information from antibodies such as PT121 and utilizing it to design an immunogen molecule that will elicit high levels of the same antibodies in patients.

While previous research determined a branch of the PGT121 antibody family, PGT121-123, will attack a vulnerable site on the virus envelope protein, the results from the current study find that another member of the family from a different lineage, PGT124, was able to maintain its grip by attaching to a small fragment of the protein plus a single glycan.

"Affinity maturation is a critical process of directed evolution in mounting an antibody response to all pathogens," said Fernando Garces, a postdoctoral fellow in the Wilson laboratory in a press release. "However, molecular details of this process have been unavailable. Now, through structural biology, we have elucidated at the atomic level how antibody maturation can pursue different strategies to recognize HIV-1 gp120, leading to broad neutralization of the virus. Initially, we had assumed that the PGT121 family has a complex epitope involving multiple protein pieces and many glycans.