Decades into the HIV epidemic, there is as yet no effective vaccine to prevent new cases. In a recent Nature Immunology article (Ray et al.), the Batista lab of the Ragon Institute has preclinically validated a new HIV immunogen design approach from the Scripps Institute’s Schief lab targeting an unexplored site on the HIV-1 Envelope protein (Env).
Most human vaccines fight infection by calling up an antibody response. While it has been observed for decades that some patients develop broadly neutralizing antibodies (bnAbs) against HIV, obtaining a protective response through vaccination has proven immensely challenging. Antibodies are secreted by B cells: when an infectious invader first enters the body, some B cells are capable of binding to parts of the invader—its antigens. These B cells may then immediately start secreting high levels of antibody or enter into a reaction called the germinal center, where B cells compete with each other for limited amounts of antigen and get selected for better and better binding, allowing them to make better and better antibodies. HIV bnAbs present challenges at every stage: in their naïve, pre-infection state, referred to as “germline,” the B cells that might be capable of eventually producing bnAbs make up a small fraction of the whole B cell repertoire, and generally do not bind well to HIV before they have undergone a long, complex process of B cell receptor (BCR) modification in the germinal centers. To correct for this, researchers have pursued a vaccine concept called “germline targeting” (GT): researchers first identify B cells which may be capable of producing bnAbs after substantial modification, and then design immunogens to activate those B cells to enter the germinal centers.
