Progress and prospects: immune responses to viral vectors

Abstract

Viral vectors are potent gene delivery platforms used for the treatment of genetic and acquired diseases. However, just as viruses have evolved to infect cells efficiently, the immune system has evolved to fight off what it perceives as invading pathogens. Therefore, innate immunity and antigen-specific adaptive immune responses against vector-derived antigens reduce the efficacy and stability of in vivo gene transfer. In addition, a number of vectors are derived from parent viruses that humans encounter through natural infection, resulting in preexisting antibodies and possibly in memory responses against vector antigens. Similarly, antibody and T-cell responses may be directed against therapeutic gene products that often differ from the endogenous nonfunctional or absent protein that is being replaced. As details and mechanisms of such immune reactions are uncovered, novel strategies are being developed, and vectors are being specifically engineered to avoid, suppress or manipulate the response, ideally resulting in sustained expression and immune tolerance to the transgene product. This review provides a summary of our current knowledge of the interactions between the immune system adeno-associated virus, adenoviral and lentiviral vectors, and their transgene products.

Figure 1

Overview of immune responses to viral vectors. Targeting specific organs, engineering viral envelopes, switching serotypes, modifying the transgene cassette, utilizing tissue-specific promoters, or immune modulation regimens can result in immune avoidance to the viral vector and transgene product, and in some cases even induce tolerance to the therapeutic gene product.

Figure 2

Activation of complement by viral vector particles. AAV capsids bind to the C3 complement proteins C3, C3b, iC3b and complement regulatory factor H, hence increasing the uptake of virus into macrophages and enhancing their activation. C3-AAV capsid interactions are direct and can therefore occur independently of antibodies against capsid. However, the classical, antibody-dependent pathway also occurs. Similar interactions between Ad vector particles and complement have also been identified.