Designing synthetic vaccines for HIV

Abstract

Despite three decades of intensive research efforts, the development of an effective prophylactic vaccine against HIV remains an unrealized goal in the global campaign to contain the HIV/AIDS pandemic. Recent characterization of novel epitopes for inducing broadly neutralizing antibodies has fueled research in the design and synthesis of new, well-defined antigenic constructs for the development of HIV envelope-directed vaccines. The present review will cover previous and recent efforts toward the design of synthetic vaccines based on the HIV viral envelope glycoproteins, with special emphasis on examples from our own laboratories. The biological evaluation of some of the most representative vaccine candidates, in terms of their antigenicity and immunogenicity, will also be discussed to illustrate the current state-of-the-art toward the development of fully synthetic HIV vaccines.

Keywords:

• AIDS
• broadly neutralizing antibody
• carbohydrates
• glycopeptides
• glycosylation
• gp120
• HIV vaccine design
• synthetic antigen

Acknowledgements

We acknowledge our colleagues of the Danishefsky laboratory whose work is presented in this manuscript. We also thank our collaborators S Munir Alam and Joseph Sodroski for their role in the design of the V1V2 glycopeptide.

Financial & competing interests disclosure

BF Haynes and SJ Danishefsky were supported by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS grant for the Center for HIV/AIDS Vaccine Immunology. SJ Danishefsky was also supported by William and Alice Goodwin and the Commonwealth Foundation for Cancer Research. A Fernández-Tejada thanks the European Commission (Marie Curie International Outgoing Fellowship) for funding. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Broadly neutralizing antibodies (BnAbs) able to neutralize multiple, diverse HIV-1 strains are only produced by approximately 20% of infected subjects after years of infection, but have not been successfully induced by current vaccines.

• It is generally agreed that a key feature of an effective HIV-1 vaccine would be its ability to elicit BnAbs, which have been shown to target conserved HIV-1 envelope regions, such as glycans and glycopeptides fragments on the gp120 glycoprotein.

• A number of BnAbs and their respective epitopes on the HIV-1 envelope have been isolated and identified, enabling the design and synthesis of carbohydrate and glycopeptide epitope mimics and their glycoconjugate immunogens for HIV vaccine development.

• Attempts to induce 2G12-like broadly neutralizing responses by using synthetic oligomannose clusters as mimics of the 2G12 epitope have been largely unsuccessful.

• Current efforts are focused on the characterization and reconstitution of the epitopes of recently identified BnAbs (PG9, PG16 and the PGT class) by designing and synthesizing homogeneous glycopeptides.

• Fully synthetic homogeneous glycopeptides corresponding to the V1V2 region of gp120 have been able to effectively mimic the PG9 epitope, showing nanomolar-affinity binding, comparable to native gp120 itself.

• These rationally designed, synthetic constructs are being evaluated in animal models for their potential as immunogens to elicit BnAbs and may be useful targets for the development of HIV-1 vaccines.

• Chemical synthesis of additional glycopeptide structures as mimics of other BnAb epitopes provides a powerful means to access homogeneous constructs for future antigenicity and immunogenicity studies. The structural–activity relationships made possible by these synthetic compounds will also enable exploration of the impact of glycosylation in promoting induction of BnAb-like specificities in a vaccination setting. Overall, this information will further direct the design of effective immunogens for HIV vaccine development.