What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Lessons from the Antibody Response to HIV-1

Abstract

Most broadly neutralizing antibodies to HIV-1 have in common an extreme degree of somatic hypermutation (SHM), which correlates with their ability to neutralize multiple viral strains. However, achieving such extreme SHM by immunization remains a challenge. Here, we discuss how antigenic variation during HIV-1 infection may work to exacerbate SHM by permitting multiple iterative cycles of affinity maturation in germinal centers, and speculate on how this could be recapitulated through vaccination.

Figure 1.

Alternative scenarios by which extended germinal center (GC) residency can lead to broadly neutralizing antibody (bnAb) development. (A) An unmutated naïve B cell (Bn) bnAb precursor enters a long-lived GC. Exposure to successive antigenic variants of the virus drives affinity maturation of the clone within the same GC reaction, until breadth is achieved. (B) GC hopping: A bnAb-prone clone enters into a GC and exits as a memory B cell (B_mem), being recalled to a second GC on exposure to a mutated antigenic variant of the virus. Successive cycles of entry and exit drive the acquisition of breadth. The two models are not mutually exclusive and, in both cases, extreme somatic hypermutation (SHM) is achieved by prolonged GC “dwell time.” However, only the second scenario can currently be elicited by vaccination with protein subunits.

Figure 2.

Nature of the “long-lived” germinal center (GC) response. A response in which GCs are observable several months after induction could result from different GC formation and disappearance kinetics. The figure illustrates three possible models. (A) Long-lived GCs: Individual GCs appear simultaneously close to the induction of the response and last until the GC reactions resolve several months later. Somatic hypermutation (SHM) load increases and clonal diversity decreases continuously as the reaction progresses. (B) Recurrent GCs: Individual GCs are short-lived, but as a GC disappears, a new one appears in the same follicle but with a different clonal composition, and possibly lower SHM load. (C) Long-lived GCs as in A are constantly being seeded by B-cell clones recruited from the outside, either from the memory or naïve pools. Diversity remains high throughout the course of the response. Importantly, cross-sectional analysis at a given time point does not allow for a clear distinction between these models.