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Characterization of human IgM and IgG repertoires in individuals with chronic HIV-1 infection.

ABSTRACT: Advancements in high-throughput sequencing (HTS) of antibody repertoires (Ig-Seq) have unprecedentedly improved our ability to characterize the antibody repertoires on a large scale. However, currently, only a few studies explored the influence of chronic HIV-1 infection on human antibody repertoires and many of them reached contradictory conclusions, possibly limited by inadequate sequencing depth and throughput. To better understand how HIV-1 infection would impact humoral immune system, in this study, we systematically analyzed the differences between the IgM (HIV-IgM) and IgG (HIV-IgG) heavy chain repertoires of HIV-1 infected patients, as well as between antibody repertoires of HIV-1 patients and healthy donors (HH). Notably, the public unique clones accounted for only a negligible proportion between the HIV-IgM and HIV-IgG repertoires libraries, and the diversity of unique clones in HIV-IgG remarkably reduced. In aspect of somatic mutation rates of CDR1 and CDR2, the HIV-IgG repertoire was higher than HIV-IgM. Besides, the average length of CDR3 region in HIV-IgM was significant longer than that in the HH repertoire, presumably caused by the great number of novel VDJ rearrangement patterns, especially a massive use of IGHJ6. Moreover, some of the B cell clonotypes had numerous clones, and somatic variants were detected within the clonotype lineage in HIV-IgG, indicating HIV-1 neutralizing activities. The in-depth characterization of HIV-IgG and HIV-IgM repertoires enriches our knowledge in the profound effect of HIV-1 infection on human antibody repertoires and may have practical value for the discovery of therapeutic antibodies.

SUBMITTER: Tian X

PROVIDER: S-EPMC9243603 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Although high-throughput sequencing and associated bioinformatics technologies have enabled the in-depth, sequence-based characterization of human immune repertoires, only a few studies on a relatively small number of sequences explored the characteristics of antibody repertoires in neonates, with contradictory conclusions. To gain a more comprehensive understanding of the human IgM antibody repertoire, we performed Illumina sequencing and IMGT/HighV-QUEST analysis of IgM heavy chain repertoire of the B lymphocytes from the cord blood (CB) of neonates, as well as the repertoire from peripheral blood of healthy human adults (HH). The comparative study revealed unexpectedly high levels of similarity between the neonatal and adult repertoires. In both repertoires, the VDJ gene usage showed no significant difference, and the most frequently used VDJ gene was IGHV4-59, IGHD3-10, and IGHJ3. The average amino acid (aa) length of CDR1 (CB: 8.5, HH: 8.4) and CDR2 (CB: 7.6, HH: 7.5), as well as the aa composition and the average hydrophobicity of the CDR3 demonstrated no significant difference between the two repertories. However, the average aa length of CDR3 was longer in the HH repertoire than the CB repertoire (CB: 14.5, HH: 15.5). Besides, the frequencies of aa mutations in CDR1 (CB: 19.33%, HH: 25.84%) and CDR2 (CB: 9.26%, HH: 17.82%) were higher in the HH repertoire compared to the CB repertoire. Interestingly, the most prominent difference between the two repertoires was the occurrence of N2 addition (CB: 64.87%, HH: 85.69%), a process that occurs during V-D-J recombination for introducing random nucleotide additions between D- and J-gene segments. The antibody repertoire of healthy adults was more diverse than that of neonates largely due to the higher occurrence of N2 addition. These findings may lead to a better understanding of antibody development and evolution pathways and may have potential practical value for facilitating the generation of more effective antibody therapeutics and vaccines.

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Characterization of human IgM and IgG repertoires in individuals with chronic HIV-1 infection.

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