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. 2018 Dec;33(6):502-514.
doi: 10.1007/s12250-018-0074-6. Epub 2018 Dec 19.

Divergent Primary Immune Responses Induced by Human Immunodeficiency Virus-1 gp120 and Hepatitis B Surface Antigen Determine Antibody Recall Responses

Li Yuan  1 , Wen-Jiang Chen  1 , Jia-Ye Wang  1   2   3 , Yan Li  1   2   3 , Dan Tian  1 , Ming-Xia Wang  1 , Hao-Tong Yu  1 , Ying-Chu Xu  1 , Di Li  1   2   3 , Min Zhuang  1   2   3 , Hong Ling  4   5   6   7
Affiliations

Divergent Primary Immune Responses Induced by Human Immunodeficiency Virus-1 gp120 and Hepatitis B Surface Antigen Determine Antibody Recall Responses

Li Yuan et al. Virol Sin. 2018 Dec.

Abstract

The development of a vaccine based on human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) that elicits potent protective antibodies against infection has been challenging. Recently, we compared the antibody production patterns of HIV-1 Env gp120 and hepatitis B virus surface antigen (HBsAg) to provide insights into how we may improve the protective efficacy of Env-based immunogens. Our previous study showed that HIV Env and HBsAg display different mechanisms of antibody elicitation and that T cells facilitate the responses to repeated immunizations. Here, to elucidate the detailed roles of primary immunization in immune memory response formation and antibody production, we immunized C57BL/6 mice with each antigen and evaluated the development of T follicular helper (Tfh) cells, germinal centers, and the memory responses involved in prime and boost immunizations. We found that after prime immunization, compared with HBsAg, gp120 induced higher frequencies of Tfh cells and programmed death (PD)-1+ T cells, greater major histocompatibility complex II expression on B cells, comparable activated B cells, but weaker germinal center (GC) reactions and memory B cell responses in the draining lymph nodes, accompanied by slower antibody recall responses and poor immune memory responses. The above results suggested that more PD-1+ T cells arising in primary immunization may serve as major contributors to the slow antibody recall response elicited by HIV-1 Env.

Keywords: Hepatitis B surface antigen (HBsAg); Human immunodeficiency virus type 1 envelope; Immune memory; Primary immune response; Programmed death-1 (PD-1).

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Conflict of interest statement

Conflict of interest

The authors have no conflict of interest.

Animal and Human Rights Statement

The whole study was approved by the Animal Care Committee of Harbin Medical University (HMUIRB20170036). All institutional and national guidelines for the care and use of laboratory animals were followed.

Figures

Fig. 1
Fig. 1
Humoral immune responses following immunization of C57BL/6 mice with gp120 and HBsAg (n = 4 per group). Mice were immunized subcutaneously with 15 μg wild-type trimeric gp120 (gp120T) or 2 μg HBsAg in AddaVax adjuvant formulation according to the immunization regimen (A). (B) The longitudinal plots of specific antibody responses to HIV-1 Bal gp120, HBsAg, and HIV-1 06044 gp120T were prepared after each immunization, and the endpoint titers are shown. Arrows indicate immunization. (C) The total IgG levels in immunized mouse serum on day 7 after each immunization were measured by quantitative ELISA. (D) Total specific antibody secreting cells (ASCs) on day 7 after prime (from 1 × 105 splenocytes) and final boost (from 2 × 104 splenocytes) were measured by B-cell ELISpot assays. Data are shown as means ± standard errors of the means (SEMs) from a single representative experiment of two independent experiments.
Fig. 2
Fig. 2
B-cell repertoire induced by prime and boost immunizations with gp120 and HBsAg (n = 4 per group). Mice were immunized with wild-type trimeric gp120 (gp120T) and HBsAg, as described in Fig. 1A, and sacrificed on days 7 and 14 after prime immunization and days 3 and 7 after the second boost. The frequencies of different B cell subsets in the dLNs were analyzed by flow cytometry. Contour plots and statistical graphs of MHC II expression on B cells (A), activated B cells (CD69+CD19+CD4−) (B), GC B cells (Fas+GL-7+CD19+CD4−) (C), and IgG1+ Bm cells (IgG1+B220+IgM−CD138−) (D) are shown. Data from a single representative experiment of two independent experiments are shown as means ± standard errors of the means.
Fig. 3
Fig. 3
T-cell repertoire induced by prime and boost immunizations with gp120 and HBsAg (n = 4 per group). Mice were immunized with wild-type trimeric gp120 (gp120T) and HBsAg, as described in Fig. 1A, and sacrificed on days 7 and 14 after prime immunization or on days 3 and 7 after the second boost. The frequencies of different T-cell subsets in the dLNs were analyzed by flow cytometry. Contour plots and statistical graphs of PD-1+ Tfh cell (PD-1+CXCR5+CD3+CD4+) (A), ICOS+ Tfh cells (ICOS+CXCR5+CD3+CD4+) (B), PD-1+CD3+CD4+ T cells (C), PD-1+CD3+ T cells (D), PD-1+CD3+CD8+ T cells (E), activated T cells (CD69+CD19−CD4+) (F), Tregs (Foxp3+CD3+CD4+) (G), Tem cells (CD44+CD62L−CD3+CD4+), and Tcm cells (CD44hiCD62L+CD3+CD4+) (H) are shown. Data from a single representative experiment of two independent experiments are shown as means ± standard errors of the means.
Fig. 3
Fig. 3
T-cell repertoire induced by prime and boost immunizations with gp120 and HBsAg (n = 4 per group). Mice were immunized with wild-type trimeric gp120 (gp120T) and HBsAg, as described in Fig. 1A, and sacrificed on days 7 and 14 after prime immunization or on days 3 and 7 after the second boost. The frequencies of different T-cell subsets in the dLNs were analyzed by flow cytometry. Contour plots and statistical graphs of PD-1+ Tfh cell (PD-1+CXCR5+CD3+CD4+) (A), ICOS+ Tfh cells (ICOS+CXCR5+CD3+CD4+) (B), PD-1+CD3+CD4+ T cells (C), PD-1+CD3+ T cells (D), PD-1+CD3+CD8+ T cells (E), activated T cells (CD69+CD19−CD4+) (F), Tregs (Foxp3+CD3+CD4+) (G), Tem cells (CD44+CD62L−CD3+CD4+), and Tcm cells (CD44hiCD62L+CD3+CD4+) (H) are shown. Data from a single representative experiment of two independent experiments are shown as means ± standard errors of the means.
Fig. 4
Fig. 4
Correlation analyses between proportions of PD-1+CD4+ T cells or PD-1+ Tfh cells and the level of specific antibody responses or IgG1+ Bm cells after the second boost immunization. Correlation analysis between the levels of specific antibodies and the proportions of PD-1+CD4+ T cells (A) or PD-1+ Tfh cells (B) on day 3 after the second boost immunization and correlations between the proportions of PD-1+CD4+ T cells and IgG1+ Bm cells (C) on day 7 after the second boost immunization in gp120- and HBsAg-immunized mice.
Fig. 5
Fig. 5
Correlation analyses between the proportions of PD-1+CD4+ T cells or PD-1+ Tfh cells and Tem cells, activated B cells, and GC B cells after prime immunization. Correlation analysis between proportions of PD-1+CD4+ T cells or PD-1+ Tfh cells with Tem cells, activated B cells, or GC B cells on day 7 after prime immunization (A–E) and the correlations between proportions of PD-1+ Tfh cells with Tem cells or GC B cells on day 14 after prime immunization (F, G) in gp120- and HBsAg-immunized mice.
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