A. Sarukhan et al., Successful interference with cellular immune responses to immunogenic proteins encoded by recombinant viral vectors, J VIROLOGY, 75(1), 2001, pp. 269-277
Vectors derived from the adeno-associated virus (AAV) have been successfull
y used for the long-term expression of therapeutic genes in animal models a
nd patients. One of the major advantages of these vectors is the absence of
deleterious immune responses following gene transfer. However, AAV vectors
, when used in vaccination studies, can result in efficient humoral and cel
lular responses against the transgene product. It is therefore important to
understand the factors which influence the establishment of these immune r
esponses in order to design safe and efficient procedures for AAV-based gen
e therapies. We have compared T-cell activation against a strongly immunoge
nic protein, the influenza virus hemagglutinin (HA), which is synthesized i
n skeletal muscle following gene transfer with an adenovirus (Ad) or an AAV
vector, In both cases, cellular immune responses resulted in the eliminati
on of transduced muscle fibers within 4 weeks. However, the kinetics of CD4
(+) T-cell activation were markedly delayed when AAV vectors were used. Upo
n recombinant Ad (rAd) gene transfer, T cells were activated both by direct
transduction of dendritic cells and by cross-presentation of the transgene
product, while upon rAAV gene transfer T cells were only activated by the
latter mechanism. These results suggested that activation of the immune sys
tem by the transgene product following rAAV-mediated gene transfer might be
easier to control than that following rAd-mediated gene transfer. Therefor
e, we tested protocols aimed at interfering with either antigen presentatio
n by blocking the CD40/CD40L pathway or with the T-cell response by inducin
g transgene-specific tolerance. Long-term expression of the AAV-HA was achi
eved in both cases, whereas immune responses against Ad-HA could not be pre
vented. These data clearly underline the importance of understanding the me
chanisms by which vector-encoded proteins are recognized by the immune syst
em in order to specifically interfere with them and to achieve safe and sta
ble gene transfer in clinical trials.