A Δ42PD1 fusion-expressing DNA vaccine elicits enhanced adaptive immune response to HIV-1: the key role of TLR4

Our plain-English summary of A Δ42PD1 fusion-expressing DNA vaccine elicits enhanced adaptive immune response to HIV-1: the key role of TLR4, by L. Cheng, X. Tang, Y. He, et al (Virology Journal, 2022).

The study

• Authors: L. Cheng, X. Tang, Y. He, B. Ju, H. Wang
• Journal: Virology Journal
• Published: 2022;19(1):174
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Since its discovery in the 1990s, the DNA vaccine has been of great interest because of its ability to elicit both humoral and cellular immune responses while showing relative advantages regarding producibility, stability and storage. However, when applied to human subjects, inadequate immunogenicity remains as the greatest challenge for the practical use of DNA vaccines. In this study, we generated a DNA vaccine Δ42PD1-P24 encoding a fusion protein comprised of the HIV-1 Gag p24 antigen and the extracellular domain of murine Δ42PD1, a novel endogenous Toll-like receptor 4 (TLR4) agonist. Using a mouse model, we found that Δ42PD1-P24 DNA vaccine elicited a higher antibody response and an increased number of IFN-γ-producing CD4 and CD8 T cells. Moreover, mice with Δ42PD1-P24 DNA vaccination were protected from a subcutaneous challenge with murine mesothelioma cells expressing the HIV-1 p24 antigen. Importantly, the Δ42PD1-mediated enhancement of immune responses was not observed in TLR4 knockout mice. Collectively, these data demonstrate that the immunogenicity and efficacy of DNA vaccines could be improved by the fusion of the extracellular domain of Δ42PD1 to target the immunogen to dendritic cells.

© 2022. The Author(s).

In plain English

This was a laboratory experiment in mice, not a study of asbestos or of human disease. The authors built two DNA vaccines carrying the HIV-1 Gag p24 antigen: one with p24 alone (P24) and one in which p24 was fused to the extracellular domain of mouse Δ42PD1, described as an endogenous TLR4 agonist. BALB/c mice received 20 μg of vaccine or empty pVAX1 vector twice, four weeks apart, injected into muscle with electroporation. The authors reported that the anti-p24 antibody response in the Δ42PD1-P24 group was almost 100-fold higher than in the P24 group, that CD8 T cell responses were 5.3-fold higher, and that CD4 T cell responses did not differ significantly. After challenge with AB1-Gag cells, a murine mesothelioma cell line expressing HIV-1 Gag, tumour growth was lower in the Δ42PD1-P24 group, and at day 21 only one tumour of negligible size was recovered from that group of eight mice. Mixing Δ42PD1 plasmid with P24 rather than fusing them gave no significant increase, and the advantage disappeared in TLR4 knockout mice.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal (mouse) laboratory experiment: DNA vaccine immunogenicity and tumour-challenge study
• Who was studied: Female BALB/c mice and TLR4 knockout C57BL/6 mice; the figure legend gives n = 15 for antibody and tetramer measurements, n = 6 for ELISpot and for the TLR4 knockout experiment, n = 8 for the tumour challenge and n = 5 for the mixture experiment; animal work approved at Shenzhen Third People's Hospital, China
• Exposure: DNA vaccines Δ42PD1-P24 (HIV-1 Gag p24 fused to the extracellular domain of mouse Δ42PD1) or P24 alone, or empty pVAX1 vector; 20 μg given intramuscularly twice at four-week intervals with electroporation
• Main results:
  • Antibody response in the Δ42PD1-P24 group was almost 100-fold higher than in the P24 group
  • CD8 T cell responses were 5.3-fold higher with Δ42PD1-P24 than with P24; CD4 T cell responses did not differ significantly between the two groups
  • Tumour growth after challenge with AB1-Gag murine mesothelioma cells was lower in the Δ42PD1-P24 group than in the P24 and pVAX1 control groups (n = 8 per group)
  • Only one tumour of negligible size was obtained from the Δ42PD1-P24 group when mice were euthanized three weeks after challenge
  • Giving Δ42PD1 as a separate plasmid mixed with the P24 vaccine gave no significant increase in antibody level or p24-specific T cell counts compared with P24 alone
  • In TLR4 knockout mice, Δ42PD1-P24 and P24 produced comparable p24-specific antibody and IFN-γ-producing T cell levels
• The authors' conclusion: The authors concluded that fusing the extracellular domain of Δ42PD1 to the antigen strengthened humoral and cellular immune responses in a TLR4-dependent way, and proposed that targeting dendritic cells via TLR4 in DNA vaccination would enhance efficacy
• Limitations the authors state:
  • The authors offered only a speculative explanation for why mixing Δ42PD1 with the vaccine failed, suggesting electroporation-induced inflammation may have masked the effect

Topics

Medical terms in this study, explained in our Lexicon: Discovery, Mesothelioma.

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