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  • Review Article
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The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus

Key Points

  • Neutralizing antibodies are the means by which most viral vaccines protect against infection or disease, including the successful subunit influenza virus vaccine.

  • Influenza virus and HIV-1 are both highly variable, globally persistent viruses. HIV-1 causes a chronic infection, as the virus continually evolves to escape host immune responses in each infected individual. Influenza virus causes an acute infection and the virus escapes host neutralizing antibodies that were elicited by previous infection or vaccination by infecting new individuals with no or low pre-existing immunity.

  • Despite the differences in how HIV-1 and influenza virus achieve global persistence, parallels can be drawn between the two viruses in regards to the challenge to elicit neutralizing antibodies against these viruses. Both viruses possess envelope glycoproteins (Envs) of similar architecture and entry-related functions that are the sole viral targets for neutralizing antibodies. For both viruses, the Envs have evolved immunogenic variable regions to divert the immune response and N-linked glycans to shield the virus from neutralizing antibodies.

  • Seasonal influenza virus vaccine production currently relies on predictions of the most likely emerging strains in a given year and, if a match to circulating virus is achieved, the vaccine is highly protective. However, for pandemic influenza virus, or avian 'flu, greater vaccine challenges related to viral diversity are faced, as it is difficult to predict which influenza virus strain may cross to the human population from the broad array of isolates that circulate in avian reservoirs.

  • Strategies to develop influenza virus vaccines that are more crossreactive and more immunogenic are therefore needed. These would have minimal requirements that are similar to those of an HIV-1 vaccine, which needs to induce crossprotective broadly neutralizing antibodies.

  • For HIV-1, structure-guided immunogen-design efforts that are based on rational re-engineering of recombinant Envs are in development. These are aimed at improving the presentation of conserved, broadly neutralizing B-cell epitopes to the immune system to better elicit broad neutralizing responses.

  • Similarities exist in the challenges of developing vaccines that induce broadly neutralizing antibodies against HIV-1 and influenza virus, which suggests that the two fields may benefit from increased exchange of approaches and concepts in regards to the elicitation of such broad responses.

Abstract

The ability to elicit broadly neutralizing antibody responses against HIV-1 is a crucial goal for a prophylactic HIV-1 vaccine. Here, we discuss the difficulties of achieving broad HIV-1 neutralization in the context of both the effective annual human influenza virus vaccine and the need to develop a pandemic influenza vaccine. Immunogen-design strategies are underway to target functionally conserved regions of the HIV-1 envelope glycoproteins, and similar strategies might be applicable to pandemic influenza virus vaccine development. Efforts to develop broadly neutralizing vaccines against either HIV-1 or influenza virus might establish a paradigm for future vaccines against highly variable pathogens.

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Figure 1: Influenza virus, HIV-1/HIV-2/SIV envelope glycoprotein coding sequences.
Figure 2: Schematic diagram of HIV-1 and influenza A virus.
Figure 3: Schematics of HIV-1 and influenza A virus and their surface proteins interacting with viral receptors.
Figure 4: Schematic diagrams of HIV-1 and influenza virus fusion and entry processes.
Figure 5: The envelope-glycoprotein-receptor-binding domains, variable regions and antigenic surfaces.

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Acknowledgements

We thank B. Hartman and M. Cichanowski at the Vaccine Research Center/National Institutes of Health for expert assistance with figures. G.K.H. is supported by grants from International AIDS Vaccine Initiative (IAVI), the Swedish International Development Agency (Sida)/Department of Research Cooperation (SAREC) and the Swedish Research Council. R.F. is supported by EU FP6, an NIH contract and the Netherlands Influenza Vaccine Research Centre (ZonMW). R.T.W. and S.P. are supported by the National Institute of Allergy and Infectious Diseases (NIAID) intramural research program, IAVI and the Bill and Melinda Gates Foundation. D.B. is supported by grants from NIH and IAVI, and J.S. is supported by grants from NIH, IAVI, the Bristol–Myers Squibb Foundation, The William A. Haseltine Foundation for the Arts and Sciences and the late William F. McCarty-Cooper.

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DATABASES

Entrez Genome

HIV-1

Entrez Protein

gp120

gp41

HA1

HA2

Glossary

Fab fragment

A fragment of an immunoglobulin that is formed when the molecule is digested with papain. The Fab fragment contains one complete light chain, part of a heavy chain and a single antigen-binding site.

Adjuvant

An agent that is mixed with an antigen and increases the immune response to that antigen following immunization.

TH2-biased immune response

The response that occurs when the cellular immune response is mainly composed of TH2 cells. There are two effector subsets of CD4+ T cells, TH1 and TH2 cells. These are characterized by distinct cytokine profiles and by functional activity. TH2 cells produce interleukin-4 (IL-4), IL-5, IL-9, IL-10, and IL-13, leading to activation of humoral immune responses. By contrast, TH1 cells produce interferon-γ, IL-2 and lymphotoxin, which support cell-mediated immunity. Appropriate differentiation of T cells into these subsets is important for mounting immune responses to pathogens, whereas an imbalance between these subsets is associated with diseases.

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Karlsson Hedestam, G., Fouchier, R., Phogat, S. et al. The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nat Rev Microbiol 6, 143–155 (2008). https://doi.org/10.1038/nrmicro1819

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