Multi-Donor Longitudinal Antibody Repertoire Sequencing Reveals the Existence of Public Antibody Clonotypes in HIV-1 Infection

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe HIV-1 envelope glycoprotein (Env) mediates receptor recognition and viral fusion and serves as the sole target of the neutralizing antibody response (, ). The developmental pathway of Env-specific antibodies has been probed previously using high-throughput sequencing (, , , , ), but such analyses have focused on single broadly neutralizing antibody (bNAb) lineages after infection. However, bNAbs comprise only a fraction of the antibody response within a given individual, which also 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 (, , , ). More generally, thorough and large-scale profiling of the repertoire-wide antibody response during the course of natural infection remains a predominantly unexplored area of investigation and an unmet need in HIV-1 research. Indeed, the extensive evidence of the global effects that HIV-1 has on the adaptive immune system, including hypergammaglobulinemia (), CD4+ T cell abnormalities (, , ), and defective CD8+ T cell function (href="#bib23" rid="bib23" class=" bibr popnode">Harrer et al., 1996, href="#bib39" rid="bib39" class=" bibr popnode">Rinaldo et al., 1995), motivates efforts to understand the dynamics of the antibody repertoires of HIV-infected individuals.Although putative bNAb precursors have been discovered in HIV-naive repertoires (href="#bib28" rid="bib28" class=" bibr popnode">Jardine et al., 2016, href="#bib47" rid="bib47" class=" bibr popnode">Yacoob et al., 2016), it is unclear how the antibody repertoires of HIV-infected individuals change from the time before infection through different stages of infection. Furthermore, while ontogeny and structural studies of HIV-reactive antibodies have revealed convergence at the structural level in multiple donors (href="#bib41" rid="bib41" class=" bibr popnode">Scheid et al., 2011, href="#bib46" rid="bib46" class=" bibr popnode">Wu et al., 2011, href="#bib51" rid="bib51" class=" bibr popnode">Zhou et al., 2015), the overall differences and similarities in the antibody repertoires of HIV-infected donors have not been characterized. Due to the diversity of potential target epitopes on Env, as well as the potentially infinite antibody sequence space resulting from gene recombination and affinity maturation, it could be expected that the antibody repertoire of each individual might be unique. Yet public antibody clonotypes that are shared among multiple individuals have been observed previously for dengue infection (href="#bib36" rid="bib36" class=" bibr popnode">Parameswaran et al., 2013), after influenza vaccination (href="#bib27" rid="bib27" class=" bibr popnode">Jackson et al., 2014), and in other immune settings (href="#bib3" rid="bib3" class=" bibr popnode">Arentz et al., 2012, href="#bib24" rid="bib24" class=" bibr popnode">Henry Dunand and Wilson, 2015, href="#bib37" rid="bib37" class=" bibr popnode">Pieper et al., 2017, href="#bib43" rid="bib43" class=" bibr popnode">Trück et al., 2015). However, in the context of HIV-1 infection the potential for public antibodies has not been explored.To better understand antibody repertoire dynamics throughout HIV-1 infection, we performed antibody repertoire sequence analysis to examine characteristics of the pre- and post-infection repertoires of multiple donors. To that end, we longitudinally sequenced the global immunoglobulin heavy chain repertoires of six South African donors from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) from before infection through acute and chronic infection. We also performed paired heavy and light chain sequencing of the Env-specific post-infection repertoires of two additional CAPRISA donors. The resulting analysis provides insights into how antibody repertoires of different individuals are reshaped during the course of HIV-1 infection.