35 lines
5.3 KiB
Markdown
35 lines
5.3 KiB
Markdown
---
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title: "Adeno-associated virus"
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chunk: 4/5
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source: "https://en.wikipedia.org/wiki/Adeno-associated_virus"
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category: "reference"
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tags: "science, encyclopedia"
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date_saved: "2026-05-05T14:17:29.244416+00:00"
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instance: "kb-cron"
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---
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==== Synthetic serotypes ====
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There have been many efforts to engineer and improve new AAV variants for both clinical and research purposes. Such modifications include new tropisms to target specific tissues, and modified surface residues to evade detection by the immune system. Beyond opting for particular strains of recombinant AAV (rAAV) to target particular cells, researchers have also explored AAV pseudotyping, the practice of creating hybrids of certain AAV strains to approach an even more refined target. The hybrid is created by taking a capsid from one strain and the genome from another strain. For example:
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Mixing AAV2 and AAV5, then undergoing directed evolution, can produce a virus that targets the respiratory tract.
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AAV2/5, a hybrid with the genome of AAV2 and the capsid of AAV5, was able to achieve more accuracy and range in brain cells than AAV2 would be able to achieve unhybridized. Researchers have continued to experiment with pseudotyping by creating strains with hybrid capsids.
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AAV-DJ has a hybrid capsid from eight different strains of AAV; as such, it can infect different cells throughout many areas of the body, a property which a single strain of AAV with a limited tropism would not have.
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Other efforts to engineer and improve new AAV variants have involved the ancestral reconstruction of virus variants to generate new vectors with enhanced properties for clinical applications and the study of AAV biology. Tags may be inserted into the AAV capsid to allow coupling of binders and improve targeting to specific cell-types or tissues.
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== Immunology ==
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AAV is of particular interest to gene therapists due to its apparent limited capacity to induce immune responses in humans, a factor which should positively influence vector transduction efficiency while reducing the risk of any immune-associated pathology.
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AAV is not considered to have any known role in disease. However, host immune system response and immune tolerance reduce the efficacy of AAV-mediated gene therapy. Host immune response has been shown to respond to the AAV vectors, the transduced cells, and the transduced proteins. The immune response can be subdivided into two categories: innate and adaptive, the latter of which is divided into humoral and cell-mediated.
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=== Innate ===
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The innate immune response to the AAV vectors has been characterised in animal models. Intravenous administration in mice causes transient production of pro-inflammatory cytokines and some infiltration of neutrophils and other leukocytes into the liver, which seems to sequester a large percentage of the injected viral particles. Both soluble factor levels and cell infiltration appear to return to baseline within six hours. By contrast, more aggressive viruses produce innate responses lasting 24 hours or longer.
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In-vivo studies indicate that AAV vectors interact with the Toll-like receptor (TLR)9- and TLR2-MyD88 pathways to trigger the innate immune response by stimulating the production of interferons. It's shown that mice deficient in TLR9 are more receptive to AAV treatment and demonstrate higher levels of transgene expression
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=== Humoral ===
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Due to previous natural infection, many people have preexisting neutralizing antibodies (NAbs) against AAV's, which can significantly hinder its application in gene therapy. Even though AAV's are highly variable among wild-type and synthetic variants, antibody recognition sites may be conserved evolutionarily.
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The virus is known to instigate robust humoral immunity in animal models and in the human population, where up to 80% of individuals are thought to be seropositive for AAV2. Antibodies are known to be neutralising, and for gene therapy applications these do impact vector transduction efficiency via some routes of administration. As well as persistent AAV specific antibody levels, it appears from both prime-boost studies in animals and from clinical trials that the B-cell memory is also strong. In seropositive humans, circulating IgG antibodies for AAV2 appear to be primarily composed of the IgG1 and IgG2 subclasses, with little or no IgG3 or IgG4 present.
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=== Cell-mediated ===
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The cell-mediated response to the virus and to vectors is poorly characterised, and has been largely ignored in the literature as recently as 2005. Clinical trials using an AAV2-based vector to treat haemophilia B seem to indicate that targeted destruction of transduced cells may be occurring. Combined with data that shows that CD8+ T-cells can recognise elements of the AAV capsid in vitro, it appears that there may be a cytotoxic T lymphocyte response to AAV vectors. Cytotoxic responses would imply the involvement of CD4+ T helper cells in the response to AAV and in vitro data from human studies suggests that the virus may indeed induce such responses, including both Th1 and Th2 memory responses. A number of candidate T cell stimulating epitopes have been identified within the AAV capsid protein VP1, which may be attractive targets for modification of the capsid if the virus is to be used as a vector for gene therapy.
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== Infection cycle ==
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There are several steps in the AAV infection cycle, from infecting a cell to producing new infectious particles: |