Persistence of HIV-1 Env-Specific Plasmablast Lineages in Plasma Cells after Vaccination in Humans

Madhubanti Basu, Michael S Piepenbrink, Czestochowa Francois, Fritzlaine Roche, Bo Zheng, David A Spencer, Ann J Hessell, Christopher F Fucile, Alexander F Rosenberg, Catherine A Bunce, Jane Liesveld, Michael C Keefer, James J Kobie, Madhubanti Basu, Michael S Piepenbrink, Czestochowa Francois, Fritzlaine Roche, Bo Zheng, David A Spencer, Ann J Hessell, Christopher F Fucile, Alexander F Rosenberg, Catherine A Bunce, Jane Liesveld, Michael C Keefer, James J Kobie

Abstract

Induction of persistent HIV-1 Envelope (Env) specific antibody (Ab) is a primary goal of HIV vaccine strategies; however, it is unclear whether HIV Env immunization in humans induces bone marrow plasma cells, the presumed source of long-lived systemic Ab. To define the features of Env-specific plasma cells after vaccination, samples were obtained from HVTN 105, a phase I trial testing the same gp120 protein immunogen, AIDSVAX B/E, used in RV144, along with a DNA immunogen in various prime and boost strategies. Boosting regimens that included AIDSVAX B/E induced robust peripheral blood plasmablast responses. The Env-specific immunoglobulin repertoire of the plasmablasts is dominated by VH1 gene usage and targeting of the V3 region. Numerous plasmablast-derived immunoglobulin lineages persisted in the bone marrow >8 months after immunization, including in the CD138+ long-lived plasma cell compartment. These findings identify a cellular linkage for the development of sustained Env-specific Abs following vaccination in humans.

Trial registration: ClinicalTrials.gov NCT02207920.

Conflict of interest statement

DECLARATION OF INTERESTS The authors declare no competing interests.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Study Design Participants (n = 22) in HVTN 105 received AIDSVAX B/E Protein (P) and DNA-HIV-PT123 plasmid (D) immunizations intramuscularly at months 0, 1, 3, and 6, according to the indicated schedule for each treatment group. Peripheral blood was collected at baseline (month 0) and 7 days (D7) after final immunization. Peripheral blood and bone marrow were collected 7–12 months after final immunization.
Figure 2
Figure 2
Boosting with AIDSVAX B/E gp120 Protein Induces Peripheral Blood Plasmablasts (A and B) Plasma (n = 22) collected at baseline and D7 following the final immunization was tested by ELISA (n = 3 replicates per dilution) for IgG specific to gp120 MN.B (A) and gp120 A244.AE (B) at 1:2500 dilution. Each bar represents mean ± SEM for an individual participant. Participant number and treatment group (T) indicated. The frequency of total IgG and gp120-specific IgG-secreting cells was determined by Elispot (n = 3 replicates per dilution). (C) Representative Elispot results from a single participant. (D) Frequency of gp120+ IgG antibody (Ab)-secreting cells (ASC) at D7 after final immunization. Bars indicate frequency for an individual participant based on triplicate Elispot wells.
Figure 3
Figure 3
Peripheral Blood Plasmablasts Express gp120-Specific Monoclonal Antibodies (mAbs) (A) Gating strategy to isolate peripheral blood plasmablasts (IgD-CD38+CD27++) D7 after final immunization. (B) Reactivity of mAbs (n = 66) to gp120 determined by ELISA (n = 3 replicates per dilution). Each line represents the mean of an individual mAb. (C) Summary of gp120 binding profiles of mAbs. (D) Summary of gp120 region-specific binding profiles of mAbs.
Figure 4
Figure 4
Plasmablast-Derived mAbs Include Those with High Avidity and ADCP Functionality (A) The avidity of the mAbs binding to gp120 in the presence of 8M urea was determined by ELISA (n = 3 replicates). Each symbol represents the avidity index for an individual mAb as determined from triplicates. (B) The Ab-dependent cellular phagocytosis of gp120-coated and BSA-coated fluorescent beads was determined at 5 μg/mL mAb. Each symbol represents the ADCP score for an individual mAb. Blue symbols denote T1 participant. (C) mAbs were serial diluted starting at 50 μg/mL and tested in duplicate for ADCC against SHIV-SF162P3.B-infected NKR24 reporter cells. (D) mAbs were serially diluted and tested in duplicate at each dilution for neutralizing activity against SF162.B pseudoviruses in the standardized TZM-bl assay.
Figure 5
Figure 5
Molecular Characteristics of Plasmablast-Derived mAbs (A) VH gene usage of mAbs isolated from indicated individual and in summary. (B) Mutation from germline for VH and VL for individual mAbs presented. (C) Length of CDR3 for heavy and light chain indicated. Blue symbols denote T1 participant. (D) Distribution of isotype usage of mAbs among each individual and in summary.
Figure 6
Figure 6
VH1 Expansion following HIV Env Vaccination Deep VH sequencing of peripheral blood IgG+ B cells isolated D7 after final immunization was performed. (A) Total number of lineages (top) and composition of specific VH gene usage among lineages (bottom) in individual participants (n = 22) within each treatment group (T1–T4). (B) Compositional representation of lineages per sample, ordered by size; VH1-2 lineages denoted in red. (C) JH usages among VH1-2 lineages and non-VH1-2 lineages. (D) HCDR3 length among VH1-2 lineages and non-VH1-2 lineages; inset number indicates number of lineages and frequency of lineages with HCDR3 length ≥ 22 amino acids. (E) VH mutation from germline; inset number indicates number of lineages and median percentage of nucleotide mutation. (F) Composition of IgG subclass usage by VH1-2 (left edge of bars) and non-VH1-2 (right edge of bars) sequences. The percentage of VH1-2 sequences per sample is shown in the bar plot at top. (G) VH mutation from germline for VH1-2 sequences from T2–T4 participants based on IgG subclass. Total number of sequences and median percentage of nucleotide mutation from germline (percentage of sequences ≥ 10% mutated from germline) are indicated.
Figure 7
Figure 7
Persistence of HIV Env-Specific Plasmablast Lineages in the BM LLPC (A) Representative Elispot of BM CD138+ LLPC for gp120, influenza, and total IgG ASCs. (B) Summary of instances of gp120+ plasmablast-derived mAb lineages identified in BM. PB, plasmablast. (C–E) Phylogenic analysis and alignments of 1105E9 (C), 1098D3/F3 (D), and 1098C4/B8 (E) lineages. Lineage members defined as same heavy-chain V and J gene usage, HCDR3 length, and ≥85% HCDR3 similarity. Red-outlined regions were analyzed for isotype usage, and those for which substantial non-IgG1 sequences were observed have an associated pie chart of isotype distribution. The germline sequence is represented by the green diamond and the mAb sequences are represented by the blue square. Alignments depict germline, mAb, and CD138+ LLPC derived sequences. The red circle (C and D) indicates the position of shared identical mutation from germline and the orange circle (E) indicates shared mutation from germline.

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Source: PubMed

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