Abstract
SummaryCharacterization of single antibody lineages within infected individuals has provided insights into the development of Env-specific antibodies. However, a systems-level understanding of the humoral response against HIV-1 is limited. Here, we interrogated the antibody repertoires of multiple HIV-infected donors from an infection-naive state through acute and chronic infection using next-generation sequencing. This analysis revealed the existence of “public” antibody clonotypes that were shared among multiple HIV-infected individuals. The HIV-1 reactivity for representative antibodies from an identified public clonotype shared by three donors was confirmed. Furthermore, a meta-analysis of publicly available antibody repertoire sequencing datasets revealed antibodies with high sequence identity to known HIV-reactive antibodies, even in repertoires that were reported to be HIV naive. The discovery of public antibody clonotypes in HIV-infected individuals represents an avenue of significant potential for better understanding antibody responses to HIV-1 infection, as well as for clonotype-specific vaccine development.
Highlights
The HIV-1 envelope glycoprotein (Env) mediates receptor recognition and viral fusion and serves as the sole target of the neutralizing antibody response (Pancera et al, 2014; Ward and Wilson, 2015)
The extensive evidence of the global effects that HIV-1 has on the adaptive immune system, including hypergammaglobulinemia (De Milito et al, 2004), CD4+ T cell abnormalities (Kaufmann et al, 2007; Palmer et al, 2004; Zhang et al, 2004), and defective CD8+ T cell function (Harrer et al, 1996; Rinaldo et al, 1995), motivates efforts to understand the dynamics of the antibody repertoires of HIV-infected individuals
The length distributions for the third heavy chain complementarity-determining region (CDRH3) remained relatively unchanged throughout infection for each donor (p > 0.1 for all CDRH3 lengths in all samples, Z test with BenjaminiHochberg correction) (Figure 1C). These results indicated that, while systems-level repertoire features were conserved over time, antibody sequence retention over the course of HIV-1 infection was low; rather, each donor was associated with virtually non-overlapping repertoires at the three different time points
Summary
The HIV-1 envelope glycoprotein (Env) mediates receptor recognition and viral fusion and serves as the sole target of the neutralizing antibody response (Pancera et al, 2014; Ward and Wilson, 2015). BNAbs comprise only a fraction of the antibody response within a given individual, which includes antibodies with limited or no breadth. These diverse antibodies are subject to viral selection pressures and host constraints, target a variety of epitopes on Env, and potentially possess functions other than neutralization (Ackerman et al, 2016; Burton and Mascola, 2015; Corey et al, 2015; Horwitz et al, 2017). The extensive evidence of the global effects that HIV-1 has on the adaptive immune system, including hypergammaglobulinemia (De Milito et al, 2004), CD4+ T cell abnormalities (Kaufmann et al, 2007; Palmer et al, 2004; Zhang et al, 2004), and defective CD8+ T cell function (Harrer et al, 1996; Rinaldo et al, 1995), motivates efforts to understand the dynamics of the antibody repertoires of HIV-infected individuals
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