AAV as An Immunogen

Abstract

The first in vivo adeno-associated viral vector (AAV) gene transfer experiments were performed in murine models of muscle directed gene transfer. These studies were remarkable for stable expression of a variety of immunogenic transgenes. These findings were translated to other target organs with multiple therapeutic gene products. Technological improvements and the lessons learned from basic research have heralded an era of first-in-human clinical trials. In most settings, AAV appears to evade host immune surveillance, allowing the delivery of robust levels of genetic cargo that leads to persistent expression. However, in few experimental settings immunological responses raised following AAV mediated gene transfer have compromised vector efficacy. Parameters that determine these occurrences have been proposed to be pre-existing immunity to AAV, the route of administration, the kinetics of expression, the dose, the vector serotype and its ability to transduce antigen-presenting cells (APCs) as well as the host species and nature of the specific transgene product. Overall, the underlying mechanisms remain the topic of scientific debate. This review aims to compile, confront and critically discuss the findings in which AAV appears to be an immunogen.

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

“…One interesting consideration was that latent AAV genomes, which occur endogenously with high abundance in humans, might have become activated by homologous recombination with vector genomes-leading to the expression of capsid proteins. 87 Nevertheless, these studies highlight the difficulties that exist in translating pre-clinical animal data to humans.…”

Distinct immune responses to transgene products from rAAV1 and rAAV8 vectors

“…The immune response to transgene products is a critical issue for successful gene therapy (3,4). While immune responses to a virally delivered antigen are highly desired for a DNA vaccine, immunogenicity may be a hurdle in gene replacement therapy for treatment of genetic diseases such as hemophilia or AAT deficiency.…”

Potential of AAV vectors in the treatment of metabolic disease

“…Variables include route of delivery, vector dose, capsid pseudo-serotype, target organ, target species and compartmentalization of the transgene product. 22,23 Natural infection with wild-type virus stimulates anti-capsid responses, detectable as serum antibodies, and preexisting immunity can impair transduction. 22 Cell-mediated responses against vector capsid have also been detected in human clinical trial subjects and healthy individuals.…”

“…25,26 Equivalent cell-mediated effects have proven difficult to replicate in small animal models, and the nature of immune mechanisms involved remains a subject of debate. 23,27 Understanding host-vector immune interactions and immunobiology of specific target organs, such as the liver, skeletal muscle and brain, will be particularly critical to the successful deployment of AAV vectors in the treatment of metabolic disease. The liver, for example, is recognized to have tolerogenic properties.…”