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Analysis of immunoglobulin transcripts and hypermutation following SHIV(AD8) infection and protein-plus-adjuvant immunization.

Francica JR, Sheng Z, Zhang Z, Nishimura Y, Shingai M, Ramesh A, Keele BF, Schmidt SD, Flynn BJ, Darko S, Lynch RM, Yamamoto T, Matus-Nicodemos R, Wolinsky D, NISC Comparative Sequencing ProgramNason M, Valiante NM, Malyala P, De Gregorio E, Barnett SW, Singh M, O'Hagan DT, Koup RA, Mascola JR, Martin MA, Kepler TB, Douek DC, Shapiro L, Seder RA - Nat Commun (2015)

Bottom Line: Here we use two nonhuman primate models to compare the roles of antigen persistence, diversity and innate immunity.The use of adjuvants results in increased ELISA titres but does not affect the mean SHM levels or CDR H3 lengths.Our study shows how the ontogeny of Env-specific B cells can be tracked, and provides insights into the requirements for developing neutralizing antibodies that should facilitate translation to human vaccine studies.

View Article: PubMed Central - PubMed

Affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
Developing predictive animal models to assess how candidate vaccines and infection influence the ontogenies of Envelope (Env)-specific antibodies is critical for the development of an HIV vaccine. Here we use two nonhuman primate models to compare the roles of antigen persistence, diversity and innate immunity. We perform longitudinal analyses of HIV Env-specific B-cell receptor responses to SHIV(AD8) infection and Env protein vaccination with eight different adjuvants. A subset of the SHIV(AD8)-infected animals with higher viral loads and greater Env diversity show increased neutralization associated with increasing somatic hypermutation (SHM) levels over time. The use of adjuvants results in increased ELISA titres but does not affect the mean SHM levels or CDR H3 lengths. Our study shows how the ontogeny of Env-specific B cells can be tracked, and provides insights into the requirements for developing neutralizing antibodies that should facilitate translation to human vaccine studies.

No MeSH data available.


Related in: MedlinePlus

VH gene correlations between Env/adjuvant vaccination and SHIVAD8 infection models.The composition of individual VH genes is graphed as the percentage of sequences mapping to each VH gene within each data set. Each dot represents an individual VH gene; diagonal lines indicate the position of genes lacking a preference between data sets. (a) HIV Env-specific compared with nonspecific sequences combined from SHIVAD8 infection and Env/adjuvant vaccination data sets. (b) Env-specific sequences from the SHIV data set compared with the Env/adjuvant vaccination data set. VH genes with enriched composition in the SHIV data set are shown in green. (c) Env-specific sequences from SHIVAD8 good neutralizers compared with poor neutralizers. VH genes with enriched composition in the good neutralizer data set are shown in red; those enriched in the poor neutralizer data set are shown in blue.
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f6: VH gene correlations between Env/adjuvant vaccination and SHIVAD8 infection models.The composition of individual VH genes is graphed as the percentage of sequences mapping to each VH gene within each data set. Each dot represents an individual VH gene; diagonal lines indicate the position of genes lacking a preference between data sets. (a) HIV Env-specific compared with nonspecific sequences combined from SHIVAD8 infection and Env/adjuvant vaccination data sets. (b) Env-specific sequences from the SHIV data set compared with the Env/adjuvant vaccination data set. VH genes with enriched composition in the SHIV data set are shown in green. (c) Env-specific sequences from SHIVAD8 good neutralizers compared with poor neutralizers. VH genes with enriched composition in the good neutralizer data set are shown in red; those enriched in the poor neutralizer data set are shown in blue.

Mentions: To address whether certain VH genes are preferentially used for Env reactivity or neutralization, a composite analysis of data obtained from both the Env vaccination and SHIVAD8 infection studies was performed. Pre-vaccination IgG sequences and nonspecific memory B cells from the SHIVAD8 infection study provided a ‘non-Env' data set (n=890,460). Env-specific reads from B cells sorted after vaccination and SHIVAD8 infection were combined for an ‘Env-specific' data set (n=58,942). The proportions of VH genes between these data sets were compared and an enrichment of specific VH genes was assessed. However, there was no preferential VH gene usage between the sequences from the Env- and non-Env-specific data sets (Fig. 6a).


Analysis of immunoglobulin transcripts and hypermutation following SHIV(AD8) infection and protein-plus-adjuvant immunization.

Francica JR, Sheng Z, Zhang Z, Nishimura Y, Shingai M, Ramesh A, Keele BF, Schmidt SD, Flynn BJ, Darko S, Lynch RM, Yamamoto T, Matus-Nicodemos R, Wolinsky D, NISC Comparative Sequencing ProgramNason M, Valiante NM, Malyala P, De Gregorio E, Barnett SW, Singh M, O'Hagan DT, Koup RA, Mascola JR, Martin MA, Kepler TB, Douek DC, Shapiro L, Seder RA - Nat Commun (2015)

VH gene correlations between Env/adjuvant vaccination and SHIVAD8 infection models.The composition of individual VH genes is graphed as the percentage of sequences mapping to each VH gene within each data set. Each dot represents an individual VH gene; diagonal lines indicate the position of genes lacking a preference between data sets. (a) HIV Env-specific compared with nonspecific sequences combined from SHIVAD8 infection and Env/adjuvant vaccination data sets. (b) Env-specific sequences from the SHIV data set compared with the Env/adjuvant vaccination data set. VH genes with enriched composition in the SHIV data set are shown in green. (c) Env-specific sequences from SHIVAD8 good neutralizers compared with poor neutralizers. VH genes with enriched composition in the good neutralizer data set are shown in red; those enriched in the poor neutralizer data set are shown in blue.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403371&req=5

f6: VH gene correlations between Env/adjuvant vaccination and SHIVAD8 infection models.The composition of individual VH genes is graphed as the percentage of sequences mapping to each VH gene within each data set. Each dot represents an individual VH gene; diagonal lines indicate the position of genes lacking a preference between data sets. (a) HIV Env-specific compared with nonspecific sequences combined from SHIVAD8 infection and Env/adjuvant vaccination data sets. (b) Env-specific sequences from the SHIV data set compared with the Env/adjuvant vaccination data set. VH genes with enriched composition in the SHIV data set are shown in green. (c) Env-specific sequences from SHIVAD8 good neutralizers compared with poor neutralizers. VH genes with enriched composition in the good neutralizer data set are shown in red; those enriched in the poor neutralizer data set are shown in blue.
Mentions: To address whether certain VH genes are preferentially used for Env reactivity or neutralization, a composite analysis of data obtained from both the Env vaccination and SHIVAD8 infection studies was performed. Pre-vaccination IgG sequences and nonspecific memory B cells from the SHIVAD8 infection study provided a ‘non-Env' data set (n=890,460). Env-specific reads from B cells sorted after vaccination and SHIVAD8 infection were combined for an ‘Env-specific' data set (n=58,942). The proportions of VH genes between these data sets were compared and an enrichment of specific VH genes was assessed. However, there was no preferential VH gene usage between the sequences from the Env- and non-Env-specific data sets (Fig. 6a).

Bottom Line: Here we use two nonhuman primate models to compare the roles of antigen persistence, diversity and innate immunity.The use of adjuvants results in increased ELISA titres but does not affect the mean SHM levels or CDR H3 lengths.Our study shows how the ontogeny of Env-specific B cells can be tracked, and provides insights into the requirements for developing neutralizing antibodies that should facilitate translation to human vaccine studies.

View Article: PubMed Central - PubMed

Affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
Developing predictive animal models to assess how candidate vaccines and infection influence the ontogenies of Envelope (Env)-specific antibodies is critical for the development of an HIV vaccine. Here we use two nonhuman primate models to compare the roles of antigen persistence, diversity and innate immunity. We perform longitudinal analyses of HIV Env-specific B-cell receptor responses to SHIV(AD8) infection and Env protein vaccination with eight different adjuvants. A subset of the SHIV(AD8)-infected animals with higher viral loads and greater Env diversity show increased neutralization associated with increasing somatic hypermutation (SHM) levels over time. The use of adjuvants results in increased ELISA titres but does not affect the mean SHM levels or CDR H3 lengths. Our study shows how the ontogeny of Env-specific B cells can be tracked, and provides insights into the requirements for developing neutralizing antibodies that should facilitate translation to human vaccine studies.

No MeSH data available.


Related in: MedlinePlus