The Implications of Broadly Neutralizing Antibody Development and Epitope Targeting for HIV Vaccine Development

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By Sean Smith

Introduction


Robert Gallo and Luc Montagnier discovered Human immunodeficiency virus to be the causative agent of Autoimmune deficiency syndrome (AIDS) in 1984 only a few years after the initial HIV outbreak across the world. However, unlike other viruses known to cause epidemics across the world, such as polio, no effective vaccine for HIV has been discovered through classical strategies. HIV’s high rate of mutation, greater than any other characterized human pathogen, is thought to be responsible for the repeated failure of attempts to develop a vaccine. Due to the high rate of mutations, the target sites of the antibodies, the epitopes, are constantly changing. Furthermore, an antibody with specific binding to a single epitope may lose its binding affinity in response to mutations in a target epitope. The decrease in binding affinity eliminates the neutralizing ability of the antibody and allows viral progression to proceed unmitigated.


However, in a select percentage of chronically infected HIV patients, potent antibodies known as broadly neutralizing antibodies have been shown to effectively bind a wide range of distinct epitopes. The increased range of binding affinity allows a single clade of similar broadly neutralizing antibodies to neutralize many distinct mutations of HIV. The characteristics of broadly neutralizing antibodies have attracted the attention of vaccine researchers who believe that a vaccine that causes the development of potent broadly neutralizing antibodies could effectively prevent early HIV infection. Research to better understand the development of HIV antibodies and the structures of their epitopes has given weight to the belief that broadly neutralizing antibodies have the potential to effectively prevent early HIV progression. The following is a summary of the current research on antibody epitopes and antibody development and of the further characterization needed to effectively translate such research into an effective vaccine.


Structures of Primary HIV Antibody Epitopes


All primary HIV antibody epitopes are found on the heterotrimer HIV envelope spike (Figure 1). The heterotrimer spike is comprised of gp41, a protein partially embedded in the HIV membrane that binds other envelope proteins, and gp120, the protein responsible for binding CCR5, CD4, or CXCR4. A complex glycan layer surrounds gp41 and gp120 to comprise much of the outer layer of the HIV spike. The range of epitopes is greatly varied. Antibodies have been found to target specific segments of the gp41 protein and the gp120 protein in both glycan shield dependent and independent manners and have been shown to depend on the quaternary structure of the spike in some instances while showing structure independent binding in other cases.

Figure 1) Here is a striking example of plastic waste accumulation in Marine Environments http://www.usgreenchamber.com/wp-content/uploads/2012/07/plastic-beach.jpg.

Four antibody epitopes on the HIV spike that have been shown to be targets for broadly neutralizing antibodies are MPER, the CD4 binding site, the V1/V2 loop and the V3 loop. The following is a summary of the known structural characteristics and of the antibodies known to target such sites. MPER (Membrane proximal external region) is a highly conserved target for neutralizing antibodies located on the gp41 protein in the base of the HIV spike. The broadly neutralizing neutralizing antibody 10E8 has been shown to bind to highly conserved hydrophobic residues of the MPER with specificity. The CD4 binding site on the gp120 spike protein is targeted by broadly neutralizing antibodies that mimic CD4 binding. The broadly neutralizing antibody VCR01 interacts with the CD4 binding site and causes a conformational shift at the binding site through its interaction. The conformational shift depresses the functionality of the receptor and therefore neutralizes the HIV virus. The V1/V2 (Variable region 1/Variable Region 2) loop on the gp120 protein is one of the most frequently mutated portions of the HIV virion. However, the V1/V2 loop has been shown to be one of the most frequent epitopes for potent broadly neutralizing antibodies. Known antibodies PG9 and VCR26 appear to rely on the conservation of quaternary structure and on the conversation of the N linked glycan at residue 160 of the V1/V2 loop heighten antibody/epitope binding affinity. The effects of the potential mutations at that site will be discussed below. The V3 (Variable region 3) loop on the gp120 plays a vital role in viral entry into the host cell. The exposed tip of the V3 loop has been targeted by neutralizing in a quaternary-structure specific manner. However, many V3 loop targeting antibodies have narrow, rather than broad, neutralizing specificity. More research on how the structure of V3 governs antibody specificity is needed.

The glycan shield surrounding gp120 and gp41 on the HIV spike plays a vital role in determining many antibody epitopes. N-linked glycans determine almost half of the mass of the HIV spike. However, very few glycan dependent or glycan specific neutralizing antibodies have been isolated and epitopes appear to be centralized on the gp120 protein and to a lesser extent at the base of the gp41 protein. Despite the fact that antibodies have not been shown to bind to the glycan shield directly, the shield can still affect antibody binding through steric hindrance. Since the glycan shield covers over half of the entire spike, it governs the how accessible specific potential epitopes are to neutralizing antibodies.

Common Mutations in the Structure of Primary Epitopes


Include some current research in each topic, with at least one figure showing data.

Figure 1) Here is a striking example of plastic waste accumulation in Marine Environments http://www.usgreenchamber.com/wp-content/uploads/2012/07/plastic-beach.jpg.

Topic 3


Include some current research in each topic, with at least one figure showing data.

Conclusion


Overall paper length should be 2,000 (Draft 1), 3,000 words (Final), with at least 3 figures.

References

[Sample reference] Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". International Journal of Systematic and Evolutionary Microbiology. 2000. Volume 50. p. 489-500.

Edited by student of Joan Slonczewski for BIOL 375 Microbiology, 2014, Kenyon College.