Abstract
Characterization of the diversified immunoglobulin (Ig) repertoire may provide insight into pathways that shape an efficient antibody (Ab) repertoire for immune response against human immunodeficiency virus (HIV) infection. This study aimed to profile characteristics of the plasmablast repertoire during chronic HIV infection. Ig variable regions of plasmablasts from both chronically HIV-infected donors (HIVDs) previously treated with antiretroviral therapy (ART) and healthy donors (HDs) were amplified by single-cell PCR to establish the basis for further repertoire analysis. We compared the plasmablast repertoires expressed in multiple chronically HIVDs after ART treatment cessation and HDs. We also examined the non-productive repertoire to identify the indication of the immediate products of the rearrangement machinery without an impact of selection during HIV infection. We found multiple differences between the productive repertoires of HIVD and HD subjects, including biased usages of VH3-49, VH1-2, VH3-33, VH3-74, and VH5-51 in VH and D1-7, D1-14, D1-20, and D5-5/18 in D segments in the HIVD group, as well as shorter and preferential glycine usages in CDRH3 regions. Gene selections were also detected in light chains. Notably, differences between productive rearrangements of HIVDs and HDs outnumbered those between productive and non-productive rearrangements within HIVDs. HIV infection may exert a dominant impact on the development of the plasmablast repertoire. The impact of selection is of limited significance in shaping the plasmablast repertoire. Overall, the data indicate that the environment in which the plasmablasts live can affect the distribution of the VH and VL genes in the repertoire and the amino acid compositions of the expressed Abs.
Highlights
Elicitation of broadly neutralizing antibody of interest via vaccination is recognized as the ultimate approach for combatting human immunodeficiency virus (HIV) infection [1]
A total of 698 VH sequences were amplified from healthy donors (HDs), consisting of 610 productive (87%) genes, while 513 VH sequences were obtained from HIV-infected donors (HIVDs), with 403 (79%) being productive
We identified a similar distribution of the Vκ and Vλ gene families in the HD and HIVD groups
Summary
Elicitation of broadly neutralizing antibody (bNAb) of interest via vaccination is recognized as the ultimate approach for combatting human immunodeficiency virus (HIV) infection [1]. An enormously diversified and non-self-reactive antibody (Ab) repertoire is the basis of a potent Ab response. The diversified Ig repertoire is generated by molecular events before antigen (Ag) encounter and, later, through somatic hypermutation and class switch recombination during Agdependent germinal center reactions [2]. There are significant gaps in our knowledge of Ig repertoires during HIV infection. Thorough profiling involving a repertoire-wide analysis to elucidate the underlying sophisticated mechanisms by which the repertoire in the context of HIV infection is ontogenetically developed and shaped remains an unmet need. A better understanding of Ig repertoire development would provide striking insights for bNAb elicitation
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