High-resolution mapping of the neutralizing and binding specificities of polyclonal sera post-HIV Env trimer vaccination
| Autor: | Keara D. Malone, Christopher A. Cottrell, Thomas J. Ketas, Per Johan Klasse, John P. Moore, Sarah K Hilton, Jesse D. Bloom, Julie Overbaugh, Payal Pratap, Adam S. Dingens, Andrew B. Ward |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
QH301-705.5 Science viruses Human immunodeficiency virus (HIV) HIV Antibodies Biology medicine.disease_cause General Biochemistry Genetics and Molecular Biology Virus 03 medical and health sciences Immunology and Inflammation 0302 clinical medicine Immune system medicine Animals Biology (General) HIV vaccine AIDS Vaccines Microbiology and Infectious Disease General Immunology and Microbiology electron microscopy polyclonal epitope mapping Env trimer immunization General Neuroscience env Gene Products Human Immunodeficiency Virus HIV polyclonal sera General Medicine Virology Vaccination 030104 developmental biology Polyclonal antibodies Infectious disease (medical specialty) mutational antigenic profiling HIV-1 biology.protein Medicine Rabbits Antibody Epitope Mapping 030217 neurology & neurosurgery Research Article |
| Zdroj: | eLife eLife, Vol 10 (2021) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.64281 |
| Popis: | Mapping polyclonal serum responses is critical to rational vaccine design. However, most high-resolution mapping approaches involve isolating and characterizing individual antibodies, which incompletely defines the polyclonal response. Here we use two complementary approaches to directly map the specificities of the neutralizing and binding antibodies of polyclonal anti-HIV-1 sera from rabbits immunized with BG505 Env SOSIP trimers. We used mutational antigenic profiling to determine how all mutations in Env affected viral neutralization and electron microscopy polyclonal epitope mapping (EMPEM) to directly visualize serum Fabs bound to Env trimers. The dominant neutralizing specificities were generally only a subset of the more diverse binding specificities. Additional differences between binding and neutralization reflected antigenicity differences between virus and soluble Env trimer. Furthermore, we refined residue-level epitope specificity directly from sera, revealing subtle differences across sera. Together, mutational antigenic profiling and EMPEM yield a holistic view of the binding and neutralizing specificity of polyclonal sera. eLife digest Vaccines work by stimulating the immune system to produce proteins called antibodies. These antibodies bind to the virus targeted by the vaccine and block the virus from infecting cells. It has been difficult to develop a vaccine for HIV because frequent mutations allow it to evade antibodies. Understanding exactly how these proteins bind to HIV and how various mutations enable the virus to escape them is crucial to designing a successful HIV vaccine. Over the last decade, scientists have developed new techniques for studying individual antibodies and how they bind to viruses. Now, they are using these insights to design vaccines. Most vaccines result in the production of many antibodies that bind to different parts of the virus, making it harder for a virus to escape. But studying many antibodies with different targets on the virus simultaneously remains challenging. By combining two-cutting edge approaches, Dingens et al. catalogued the many antibodies that rabbits produce in response to an experimental vaccine for HIV. In the experiments, they mapped how two types of rabbit antibodies target the virus: those that could bind to the virus, and those that could both bind and neutralize the virus (i.e., block it from infecting cells). The experiments showed that small differences between the HIV virus and the vaccine explained why some rabbit antibodies created in response to the vaccine could bind but not neutralize the virus. Moreover, the ability to stop HIV from infecting the cells appeared to be reserved to antibodies that could bind to several different locations at the virus. Dingens et al. further documented all the virus mutations that would allow it to evade neutralizing antibodies. The techniques used in the experiments may help scientists identify the best sites on the HIV virus to target with vaccines and to better understand the binding and neutralizing activity of antibodies. The results of the experiments may also help to redesign the experimental HIV vaccine – which is currently being tested in humans – to be even more effective. |
| Databáze: | OpenAIRE |
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