In 1981 the Human Immunodeficiency Virus (HIV) first emerged in the United States1. In the intervening years a tremendous effort has been made to eradicate HIV and AIDS. With the advent of retroviral therapies, HIV can be controlled for decades, drastically increasing the lifespan of those suffering from this infection.
However, as these HIV+ individuals age, they become increasingly at risk of developing other medical issues, such as HIV associated neurological disorders (HAND). A vaccination to impede the spread of this virus is still greatly needed and highly sought after within the field.
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There are many challenges in developing a vaccine for HIV, particularly its high rate of mutation and large number of strains in circulation. Indeed, many vaccines have been tested over the years; all of which have failed except one, RV144. Using the wisdom of previously successful subunit vaccines for other viruses, such as tetanus, researchers found that the correct use of a single viral protein or protein subunit was sufficient to induce the production of protective antibody titers within the human body.
Unfortunately, the first two attempts at subunit-based vaccination of HIV did not succeed. These studies attempted to induce cell mediated immune responses towards HIV proteins. The trials were not successful in doing so, and in one case the vaccine may even have increased risk of contracting HIV in homosexual men2.
These unsuccessful trials employed a homologous prime-boost method, in which the same vaccination is given multiple times in order to “boost” the immune response against the antigen and therefore the virus as well. This multi-dose regimen is known to increase the efficacy of many vaccines, and is commonly used (e.g. tetanus booster). However, it has been shown that a heterologous prime-boost strategy, wherein the boost vaccinations are performed using alternate delivery methods, can be even more effective3.
The first HIV vaccine to show efficacy in a phase 3 trial was RV144, which employed a heterologous prime-boost methodology. This trial showed that within 1 year of immunization, 60% efficacy was observed, although this success rate dropped to 31% by the endpoint of the study, which was 3.5 years later4. This success has generated excitement in the field, but implies that there is still significant room for improvement in future vaccine development.
Thus, researchers such as Dr. Mohammed Aiyegbo, of the New York University, aim to determine what factors contributed to the success of RV144. By elucidating the mechanism and key players involved in reducing the risk of HIV contraction, future HIV vaccines may one day share a success story as inspiring as that of the Polio vaccine.
In his recent paper, published in the journal PLoS One, Dr. Aiyegbo and colleagues determined the structural conformation of a small peptide known to be targeted by protective antibodies that are generated during RV144 vaccination5. By understanding the structure of this molecule, they hope to aid the development of antibodies which provide more robust and more consistent protection against the virus.
The authors of this paper performed nuclear magnetic resonance (NMR), using a Bruker AVANCE II spectrometer, in order to determine the structure of this protection-associated peptide. By including NMR data into computer algorithms designed to rapidly predict the many possible conformations a protein sequence can physically undergo, the authors were able to determine that the most energetically favorable structure was that of a flexible alpha-helix. This information will allow other researchers in the field to develop antibodies that more effectively target this peptide, not only based upon its sequence, but its structure as well.
By using the Bruker AVANCE II spectrometer to perform NMR, researchers are able to determine the structure of a protein in solution, which is not possible with x-ray crystallography6. This allows for a potentially more physiologically relevant, as well as a more dynamic, understanding of the conformation(s) observed. The versatility of NMR lends it a wide range of possible applications, including both drug target studies, as described above, as well as rational drug design efforts, among many others.
Dr. Aiyegbo and his colleagues have demonstrated the importance of this technique with their study elucidating the flexible structure of an HIV protection-associated peptide. The authors posit that this novel understanding will lead to future improvements in the design of vaccinations against HIV, an undertaking which may benefit from the use of NMR spectroscopy as well.
References:
- Girard, Marc P., Saladin Osmanov, Olga M. Assossou, and Marie-Paule Kieny. "Human Immunodeficiency Virus (HIV) Immunopathogenesis and Vaccine Development: A Review." Vaccine 29.37 (2011): 6191-218.
- Kim JH, Rerks-Ngarm S, Excler JL, Michael NL. HIV vaccines: lessons learned and the way forward. Curr Opin HIV AIDS. 2010; 5(5):428–34.
- Lu, Shan. "Heterologous Prime Boost Vaccination." Current Opinion in Immunology 21.3 (2009): 346-51.
- Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. NEngl J Med. 2009; 361(23):2209–20.
- Aiyegbo, Mohammed S., Evgeny Shmelkov, Lorenzo Dominguez, Michael Goger, Shibani Battacharya, Allan C. Decamp, Peter B. Gilbert, Phillip W. Berman, and Timothy Cardozo. "Peptide Targeted by Human Antibodies Associated with HIV Vaccine-Associated Protection Assumes a Dynamic α-Helical Structure." Plos One 12.1 (2017)
- Ambrus, Attila. "Comparison of NMR and X-ray Crystallography." Comparison of NMR and X-ray Crystallography.
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