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Targeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses.

Publication ,  Journal Article
Melchers, M; Bontjer, I; Tong, T; Chung, NPY; Klasse, PJ; Eggink, D; Montefiori, DC; Gentile, M; Cerutti, A; Olson, WC; Berkhout, B; Moore, JP ...
Published in: J Virol
March 2012

An HIV-1 vaccine remains elusive, in part because various factors limit the quantity and quality of the antibodies raised against the viral envelope glycoprotein complex (Env). We hypothesized that targeting Env vaccines directly to B cells, by fusing them to molecules that bind and activate these cells, would improve Env-specific antibody responses. Therefore, we fused trimeric Env gp140 to A PRoliferation-Inducing Ligand (APRIL), B-cell Activating Factor (BAFF), and CD40 Ligand (CD40L). The Env-APRIL, Env-BAFF, and Env-CD40L gp140 trimers all enhanced the expression of activation-induced cytidine deaminase (AID), the enzyme responsible for inducing somatic hypermutation, antibody affinity maturation, and antibody class switching. They also triggered IgM, IgG, and IgA secretion from human B cells in vitro. The Env-APRIL trimers induced higher anti-Env antibody responses in rabbits, including neutralizing antibodies against tier 1 viruses. The enhanced Env-specific responses were not associated with a general increase in total plasma antibody concentrations, indicating that the effect of APRIL was specific for Env. All the rabbit sera raised against gp140 trimers, irrespective of the presence of CD40L, BAFF, or APRIL, recognized trimeric Env efficiently, whereas sera raised against gp120 monomers did not. The levels of trimer-binding and virus-neutralizing antibodies were strongly correlated, suggesting that gp140 trimers are superior to gp120 monomers as immunogens. Targeting and activating B cells with a trimeric HIV-1 Env-APRIL fusion protein may therefore improve the induction of humoral immunity against HIV-1.

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Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

March 2012

Volume

86

Issue

5

Start / End Page

2488 / 2500

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Virology
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • Recombinant Fusion Proteins
  • Rabbits
  • Protein Multimerization
  • Neutralization Tests
  • Humans
  • HIV-1
  • HIV Infections
 

Citation

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Melchers, M., Bontjer, I., Tong, T., Chung, N. P. Y., Klasse, P. J., Eggink, D., … Sanders, R. W. (2012). Targeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses. J Virol, 86(5), 2488–2500. https://doi.org/10.1128/JVI.06259-11
Melchers, Mark, Ilja Bontjer, Tommy Tong, Nancy P. Y. Chung, Per Johan Klasse, Dirk Eggink, David C. Montefiori, et al. “Targeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses.J Virol 86, no. 5 (March 2012): 2488–2500. https://doi.org/10.1128/JVI.06259-11.
Melchers M, Bontjer I, Tong T, Chung NPY, Klasse PJ, Eggink D, et al. Targeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses. J Virol. 2012 Mar;86(5):2488–500.
Melchers, Mark, et al. “Targeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses.J Virol, vol. 86, no. 5, Mar. 2012, pp. 2488–500. Pubmed, doi:10.1128/JVI.06259-11.
Melchers M, Bontjer I, Tong T, Chung NPY, Klasse PJ, Eggink D, Montefiori DC, Gentile M, Cerutti A, Olson WC, Berkhout B, Binley JM, Moore JP, Sanders RW. Targeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses. J Virol. 2012 Mar;86(5):2488–2500.

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

March 2012

Volume

86

Issue

5

Start / End Page

2488 / 2500

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Virology
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • Recombinant Fusion Proteins
  • Rabbits
  • Protein Multimerization
  • Neutralization Tests
  • Humans
  • HIV-1
  • HIV Infections