Abstract
The exploitation of various human immunodeficiency virus type-1 (HIV-1) vaccines has posed great challenges for the researchers in precisely evaluating the vaccine-induced immune responses, however, the understanding of vaccination response suffers from the lack of unbiased characterization of the immune landscape. The rapid development of high throughput sequencing (HTS) makes it possible to scrutinize the extremely complicated immunological responses during vaccination. In the current study, three vaccines, namely N36, N51, and 5-Helix based on the HIV-1 gp41 pre-hairpin fusion intermediate were applied in rhesus macaques. We assessed the longitudinal vaccine responses using HTS, which delineated the evolutionary features of both T cell and B cell receptor repertoires with extreme diversities. Upon vaccination, we unexpectedly found significant discrepancies in the landscapes of T-cell and B-cell repertoires, together with the detection of significant class switching and the lineage expansion of the B cell receptor or immunoglobulin heavy chain (IGH) repertoire. The vaccine-induced expansions of lineages were further evaluated for mutation rate, lineage abundance, and lineage size features in their IGH repertoires. Collectively, these findings conclude that the N51 vaccine displayed superior performance in inducing the class-switch of B cell isotypes and promoting mutations of IgM B cells. In addition, the systematic HTS analysis of the immune repertoires demonstrates its wide applicability in enhancing the understanding of immunologic changes during pathogen challenge, and will guide the development, evaluation, and exploitation of new generation of diagnostic markers, immunotherapies, and vaccine strategies.
Highlights
After 36 years since HIV was discovered, conquering human immunodeficiency virus type-1 (HIV-1) still remains a challenge for mankind
The highthroughput sequencing (HTS) has changed the way we look at immune repertoires and vaccine design [18]
We identified newly emerged high-ranking immunoglobulin heavy chain (IGH) lineages at D7 and D10 that were among the most abundant lineages in samples from other vaccination groups, implying potential functional relevance in the vaccine-induced immune response (Supplementary Figure 1). These results demonstrated that the TCR repertoire was relatively stable after vaccine boosting, in terms of the frequency dynamic of the most abundant TCR clones, while the IGH repertoire underwent dramatic transformations, explaining the previously illustrated overall differences observed in Complementarity determining region 3 (CDR3) numbers, Shannon index, HCN, and the top 100 cumulative clone frequency
Summary
After 36 years since HIV was discovered, conquering HIV-1 still remains a challenge for mankind. As none of the vaccines have succeeded, to date, in controlling HIV, the Highly Active Anti-Retroviral therapy (HAART) remains the hallmark of treatment for HIV patients Drugs such as fusion, protease, reverse transcriptase, and integrase inhibitors [1, 2] can block the virus life cycle at different steps of infection process. The HTS has provided many useful insights into mechanisms of immune responses through repertoire analysis [19,20,21], along with its potential clinical applications in the identification of new generation of biomarkers [22], therapeutic antibody design [23], and future design of anti-HIV vaccines. The methodology of sequencing data analysis provides novel alternatives for a traditional vaccine study
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