What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination?

Abstract

A key goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs) targeted to the vulnerable regions of the HIV envelope. BnAbs develop overtime in ∼50%of HIV-1-infected individuals. However, to date, no vaccines have induced bnAbs and few or none of these vaccine-elicited HIV-1 antibodies carry the high frequencies of V(D)J mutations characteristic of bnAbs. Do the high frequencies of mutations characteristic of naturally induced bnAbs represent a fundamental barrier to the induction of bnAbs by vaccines? Recent studies suggest that high frequencies of V(D)J mutations can be achieved by serial vaccination strategies. Rather, it appears that, in the absence of HIV-1 infection, physiologic immune tolerance controls, including a germinal center process termed affinity reversion, may limit vaccine-driven bnAb development by clonal elimination or selecting for mutations incompatible with bnAb activity.

HIV-1 Envelope Recognition by Polyreactive and Cross-Reactive Intestinal B Cells

“…The loss of regulatory T cells and/or their anergy-prone state is certainly a key factor facilitating the emergence of autoreactive B cell clones during HIV-1 infection ( Moody et al., 2016 ). Clones expressing a B cell receptor with a dual reactivity to HIV-1 and self-antigens could also be redeemed from tolerance purge via the selection of antibody mutations’ increasing affinity to HIV-1 Env but disfavoring high autoantigen binding ( Burnett et al., 2018 , Kara and Nussenzweig, 2018 , Kelsoe and Haynes, 2018 ). Accumulating data from human ( Reed et al., 2016 , Sabouri et al., 2014 , Tan et al., 2016 ) and mouse models ( Sabouri et al., 2014 , Burnett et al., 2018 ) converge toward the existence of such a “B cell redemption” mechanism, which permits the recruitment of autoreactive clones during the germinal center reaction in response to natural infection or vaccination.…”

Env Exceptionalism: Why Are HIV-1 Env Glycoproteins Atypical Immunogens?

“…A key aspect of bNAb epitopes is that they often comprise both peptidic and glycan components; all the known ones on gp120 include, or even consist entirely of, glycans (Crispin et al, 2018;Lee et al 2017;Ward and Wilson, 2017). Given that glycans are largely seen as ''self'' by the immune system, their immunogenicity requires the breaking of tolerance (Kelsoe and Haynes, 2018). In short, the high titers of non-NAbs or NAbs that act only against highly sensitive (Tier-1) viruses, which are common endpoints in animal studies and clinical trials, are not useful for assessing Env immunogenicity.…”

Immune Responses to Retroviruses

“…Although the circumstances that lead to the development of these broadly neutralizing antibodies in a minority of the HIV-1 infected population remain unclear, high antigen exposure appears to be a major determinant as the appearance of these antibodies is observed after several years of uncontrolled infection and/or in infected subjects with high levels of viremia (159). The rarity of this phenomenon appears to be related to the need to accumulate an extraordinary rate of mutations (160), 5-10 times higher than for other pathogens (161), to acquire HIV broadly neutralizing capacity. As in the case of the T cell response, alterations in the secondary lymphoid organs provoked by HIV-1 infection may decisively alter the development of the antibody response.…”