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neutralization

TWiV 866: EV antibodies rEVolutionize our thinking

15 February 2022 by Vincent Racaniello

Amy returns to TWiV to discuss her work on the identification of cross-reactive antibody responses among diverse enteroviruses, and the implications for our understanding of viral pathogenesis and seroprevalence studies.

Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit Brianne Barker, and Amy Rosenfeld

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Show notes at microbe.tv/twiv

Filed Under: This Week in Virology Tagged With: antibody, cross-reactive antibody, enterovirus, epitope, neutralization, plaque assay, poliovirus, serology

TWiV 332: Vanderbilt virology

12 April 2015 by Vincent Racaniello

On episode #332 of the science show This Week in Virology, Vincent visits Vanderbilt University and meets up with Seth, Jim, and Mark to talk about their work on a virus of Wolbachia, anti-viral antibodies, and coronaviruses.

You can find TWiV #332 at www.microbe.tv/twiv.

Filed Under: This Week in Virology Tagged With: antibodies, bacteriophage, coronavirus, ebolavirus, endosymbiont, error correction, evolution, influenza virus, MERS, mutation, neutralization, SARS, viral, virology, virus, wolbachia

TWiV 319: Breaking breakbone

11 January 2015 by Vincent Racaniello

On episode #319 of the science show This Week in Virology, the TWiVers review the outcomes of two recent phase 3 clinical trials of a quadrivalent dengue virus vaccine in Asia and Latin America.

You can find TWiV #319 at www.microbe.tv/twiv.

Filed Under: This Week in Virology Tagged With: attenuated, breakbone fever, clinical trial, Dengue, flavivirus, neutralization, phase 3 clinical trial, severe dengue, vaccine, viral, virologically confirmed dengue, virology, virus, yellow fever virus

Futures in Biotech 71: Genomics, Proteomics, Cellular Immunity, and Anti-Matter

30 November 2010 by Vincent Racaniello

I joined Marc Pelletier, Andre Nantel, and George Farr on futures-in-biotechepisode 71 of Futures in Biotech for a conversation about the 1000 genome project, the billion dollar human proteome, how antibodies block viral infection, and capturing anti-matter.

[audio:http://www.podtrac.com/pts/redirect.mp3/twit.cachefly.net/fib0071.mp3 | titles=FiB 71]

Download audio FiB #71 (42 MB .mp3, 87 minutes)

Download video (211 MB .mp4)

Filed Under: Basic virology, Information Tagged With: antibody, neutralization, trim21, viral, virology, virus

Antibodies neutralize viral infectivity inside cells

11 November 2010 by Vincent Racaniello

Antibodies are an important component of the host defense against viral infection. These molecules, produced 7-14 days after infection, neutralize viral infectivity, thereby limiting the spread of infection. Antibodies are thought to neutralize viral infectivity in several ways: by forming noninfectious aggregates that cannot enter cells, or by blocking virion attachment to cells or uncoating (figure). A new mechanism has just joined this list, in which antibody bound virions are degraded in the cell cytoplasm.

A cytoplasmic protein called TRIM21 (tripartite motif-containing 21) was recently found to bind with high affinity to the conserved regions of antibody molecules. The presence of this activity in many mammalian species suggested that there could be ways that antibodies operate within cells. This possibility was studied by using adenovirus infection of cultured cells. When adenovirions were mixed with neutralizing antibodies and added to cells, the antibody-coated particles entered the cytoplasm where they became associated with TRIM21. This behavior was observed when several different adenovirus antibodies were used, suggesting that it is not an unusual property of one type of antibody.

By definition, neutralizing antibodies reduce viral infectivity. When levels of cellular TRIM21 protein were depleted, neutralizing antibodies had little effect on adenovirus infectivity. This effect was found in several cell lines, using three different anti-adenovirus antibodies, and requires the antibody Fc domain. These observations show that adenovirus neutralization by antibodies occurs in the cell cytoplasm, and is dependent upon the binding of antibodies to TRIM21 protein.

How does the interaction of TRIM21 with antibodies bound to adenovirus neutralize viral infectivity? TRIM21 is known to target proteins for degradation by linking them to a small protein called ubiquitin, which labels them for elimination. Cells have two different pathways for degrading ubiquitinated proteins: autophagy and the proteasome. Neutralization of antibody-coated adenovirus was not affected by an inhibitor of autophagy, but was blocked by a proteasome inhibitor. Consistent with this observation, antibody-coated adenovirions in the cell cytoplasm contained both TRIM21 and ubiquitin. Such virions are rapidly degraded, destroying their infectivity.

When antibodies were introduced in uninfected cells, they still associated with TRIM21 protein. This observation means that a virus particle is not needed for the interaction of TRIM21 with antibody. The importance of this finding is that it is possible that other viruses are neutralized by a TRIM21-dependent mechanism. Answering this question could have practical value, because stimulation of TRIM21 immunity might be an important property of effective vaccines.

TRIM21 is an example of a protein that bridges the innate and adaptive immune responses. It is induced by interferons, which are produced early in infection as foreign molecules are detected by the innate immune system. Furthermore, TRIM21 assists in viral neutralization by binding to antibodies, which are products of the adaptive immune response. As would be expected, antibody neutralization of adenovirus is more efficient when cells are treated with interferon.

The participation of cytoplasmic TRIM21 in antibody-mediated virus neutralization might explain a variety of previously unexplained observations. These include:

  • There is a linear-log relationship between antibody dilution and neutralization of adenovirus, and longer incubation does not result in more neutralization
  • Antibody neutralization of poliovirus is observed even when antibodies are added after attachment of virions to cells
  • A single IgG antibody molecule is enough to neutralize poliovirus and adenovirus infectivity
  • 5-6 IgG molecules are enough to neutralize rhinovirus
  • Intact antibody molecules are more effective at neutralizing viruses than those which have been cleaved to produce Fab and Fc fragments

It has always been difficult to understand how just a few antibody molecules can neutralize viral infectivity. The TRIM21 dependent mechanism provides the first plausible mechanism.

An important issue that is not addressed by these studies is the relationship between viral entry and TRIM21 mediated neutralization. Adenovirus is taken into the cell by endocytosis, and then released into the cytoplasm as a partially disassembled particle which docks onto the nuclear pore complex, leading to entry of DNA into the nucleus. Does TRIM21 accompany the virion throughout the endocytic process, targeting the capsid to the proteasome after it is released from the endosome? If TRIM21 were shown to be involved in neutralization of poliovirus, it would not be consistent with the observation that poliovirions do not exit endosomes – the viral RNA is simply translocated across the endosome membrane.

TRIM21-dependent antibody neutralization of viruses is a fascinating new mechanism that could apply to a wide range of viruses. But a number of questions must be answered before it enters the virology textbooks.

Mallery DL, McEwan WA, Bidgood SR, Towers GJ, Johnson CM, & James LC (2010). Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proceedings of the National Academy of Sciences of the United States of America PMID: 21045130

Filed Under: Basic virology, Information Tagged With: antibody, immune defense, immunity, immunology, neutralization, proteasome, TRIM, ubiquitin, viral, virology, virus

Virus neutralization by antibodies

24 July 2009 by Vincent Racaniello

The antibody response is crucial for preventing many viral infections and may also contribute to resolution of infection. When a vertebrate is infected with a virus, antibodies are produced against many epitopes on multiple virus proteins. A subset of these antibodies can block virus infection by a process that is called neutralization.

Antibodies can neutralize viral infectivity in a number of ways, as summarized in the illustration. They may interfere with virion binding to receptors, block uptake into cells, prevent uncoating of the genomes in endosomes, or cause aggregation of virus particles. Many enveloped viruses are lysed when antiviral antibodies and serum complement disrupt membranes.

antibody-neutralization

Non-neutralizing antibodies are also produced after viral infection. Such antibodies bind specifically to virus particles, but do not neutralize infectivity. They may enhance infectivity because antibodies can interact with receptors on macrophages. The entire virus-antibody complex is brought into the cell by endocytosis. Viral replication can then proceed because the antibody does not block infectivity. This pathway may allow entry into cells which normally do not bear specific virus receptors.

Where in the body does antibody neutralization of viruses take place? Virions that infect mucosal surfaces encounter secretory IgA antibodies present at the apical surfaces of epithelial cells. Viruses that spread in the blood will be exposed to IgG and IgM antibodies. In fact, the type of antibody that is produced can influence the outcome of viral infection. Infection with poliovirus causes IgM and IgG responses in the blood, but mucosal IgA is vital for blocking infection. This antibody can neutralize poliovirus in the intestine, the site of primary infection. The live attenuated Sabin poliovirus vaccine is effective because it elicits a strong mucosal IgA response and provide intestinal immunity.  In contrast, the injected (Salk) polio vaccine does not produce intestinal immunity, and therefore is less effective at preventing spread of poliovirus in a population.

The vast majority of influenza vaccines are administered by injection and stimulate the production of IgG antibodies; they are poor inducers of mucosal IgA antibodies. The efficacy of influenza vaccines would likely be markedly improved if they could be designed to stimulate mucosal immunity. Flumist is a licensed, intranasally-administered infectious virus vaccine that has been shown to stimulate both mucosal and systemic immunity. Nine clinical trials have been conducted in children comparing the efficacy of Flumist with inactivated vaccine or placebo. An analysis of the results suggests that the intranasally administered vaccine is more effective in preventing influenza. These results underscore the role of local immunity in resistance to respiratory pathogens.

Rhorer, J., Ambrose, C., Dickinson, S., Hamilton, H., Oleka, N., Malinoski, F., & Wittes, J. (2009). Efficacy of live attenuated influenza vaccine in children: A meta-analysis of nine randomized clinical trials Vaccine, 27 (7), 1101-1110 DOI: 10.1016/j.vaccine.2008.11.093

Filed Under: Basic virology, Information Tagged With: flumist, H1N1, IgA, IgG, IgM, influenza, neutralization, swine flu, vaccine, viral, virology, virus

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