On the benefits of sin

Abstract

Antibodies (Abs) induced during infections with immunodeficiency viruses are subject to a form of original antigenic sin, termed repertoire freeze. This phenomenon encompasses conditions in which antigen (Ag)-specific B-cells and free Ab induced against early viral variants recognize viral escape mutants sufficiently to compete for Ag with naïve B-cells. As previously activated Ag-specific Abs and B-cells are more abundant than their naïve counterparts, they out-compete naïve B-cells and can be selected to undergo repeated rounds of somatic hypermutation and affinity maturation that drive repeated rounds of immune selection and viral escape. This situation prevents or diminishes the ability of B-cells carrying novel Ab-specificities to become activated and produce free Ab, facilitating viral escape. The enactment of repertoire freeze is illustrated in several features of anti-HIV antibodies, including persistently skewed κ/λ light chain ratios, preferential variable region gene usage, and the accumulation of Abs with extensive mutations within their variable regions. Furthermore, several investigators documented the presence of anti-viral Abs carrying a common idiotype, designated 1F7, from early infection onwards. In fact, anti-idiotypic suppression of these Abs in SHIV-infected rhesus macaques allowed the development of Abs that more effectively neutralized autologous contemporaneous viruses. Although most research suggests that repertoire freeze is undesirable for controlling an active infection, recent evidence has demonstrated that potentially protective broadly neutralizing Abs (BnAbs) develop within the freeze susceptible 1F7-idiotypic repertoire. This observation suggests that repeated rounds of selection of 1F7-idiotypic Abs may drive the extensive variable region mutation that characterizes BnAbs. In this review, we address how the demonstrated overlap between 1F7-idiotypic repertoire freeze and potentially protective Ab responses can be unravelled to generate novel vaccine concepts. Furthermore, we address how idiotypic regulation of the humoral immune response could be useful for sustaining protective Ab responses.

Keywords: :

• 1F7
• HIV
• repertoire freeze
• BnAbs

Conflict of Interest

The authors declare a conflict of interest. MSP, SM, HK, and MDG are members of the scientific advisory board for Network Immunology Inc.

Funding

This work was supported by a grant from the Canadian Institutes for Health Research (CIHR) #HVI 79515 and the Fonds de la Recherche en Santé du Québec (FRSQ) AIDS and Infectious Diseases Network. M.S.P is supported by a CIHR Vanier Scholarship.

Acknowledgments

We wish to acknowledge Geoffrey W Hoffmann, chief scientist of Network Immunology Inc., for his assistance in preparing this manuscript.