Input Virion Proteins: Cryptic Targets of Antivector Immune Responses in Preimmunized Subjects

Abstract

er strongly suggest that the turnover of virion input proteins may determine whether infected cells will be targeted by antivector T cells—and if so, for how long [2,5,6,11,12]. If a subject has been previously exposed to the parent virus or vector, then the immune system has already been ‘armed’ to recognize specific antigenic epitopes. In this case, injected vector virions will be targeted rapidly by the immune system as soon as they enter the body (by circulating antibodies), or they will be metabolized and presented on MHC molecules on transduced cells. Data from several laboratories using adenoviral or AAV vectors in different target tissues indicate that the turnover of input virion proteins correlates with, and may causally determine, the persistence of transgene expression in preimmunized subjects (Fig. 1). Injection of first generation adenoviral vectors into the brain of previously immunized rats is characterized by a reduction in transgene expression of over 90% within two weeks [2]. However, injection of high-capacity adenoviral vectors (HC-Ad) into similar animals leads to persistent transgene expression for at least two months (Fig. 1a; [2]; reviewed in [13]). The main difference between these vectors is that first generation Ad continues to express viral proteins, whereas HC-Ad does not. However, infection with HC-Ad will lead to immune presentation of viral proteins, but these are exclusively derived from input virions [14]. Once this limited source of antigenic epitopes has been metabolized and turned over, the HC-Ad genomes become invisible to the immune system. Therefore, immediately upon injection of HC-Ad into preimmunized animals, virion-derived proteins provide antigenic epitopes to activated T cells. However, this is a self-limiting process, since the capacity of activated T cells to encounter infected cells and reduce transgene expression is transient. Surprisingly, while injection of HC-Ad (derived from Ad5) results in long-term expression in subjects preimmunized against adenovirus [2,3], gene expression from AAV2 vectors is greatly reduced in animals preimmunized against this vector [4-6,15]. In comparison, even first generation adenoviral vectors [16], and herpes simplex virus (HSV) vectors [17], can achieve efficient gene transfer and expression in preimmunized subjects. The nearly complete inhibition of AAV2 expression in preimmunized animals is somewhat unexpected, because in the case of adenovirus, HSV-derived vectors, [2,3,16,17], and lentiviral vectors (unpublished observations), preimmunization is unable to eliminate vector entry and transgene expression. Neutralizing antibodies are PERSPECTIVE