Extensive Cross-Reactivity of Adenovirus-Specific Cytotoxic T Cells

Abstract

Although adenovirus is a major source of morbidity for immunocompromised individuals and a popular vector for gene therapy, little is known about the cellular immune responses it evokes in humans. Initial trials using adenovirus vectors have been disappointing, probably owing both to a preexisting immune response to Ad2 and Ad5, the most commonly used vector backbones, and to a response to the transgene. The former problem might be overcome by switching from the common type C adenoviruses, of which Ad2 and Ad5 are members, to other less common serotypes. Evidence for the feasibility of this approach has been provided by a rat model system. However, its success in humans depends on there being no immunological cross-reactivity between groups at the humoral or cellular level. Here, we examine the cross-reactivity of the cellular immune response to adenovirus in a human system, and find that human cytotoxic T lymphocytes (CTLs) prepared in vitro against an adenovirus from two of the six subgroups can lyse cells infected with adenoviruses from the other subgroups. Hence, the proposed use of adenovirus vectors from uncommon subgroups to evade memory immune response to subgroup C adenoviruses may not be successful. However, this same cross-reactivity indicates that adoptive transfer of CTLs generated in vitro against one adenovirus serotype may protect immunocompromised patients from infections by adenoviruses of all serotypes.

Adenovirus hexon T-cell epitope is recognized by most adults and is restricted by HLA DP4, the most common class II allele

“…Although most Ad vectors are E1 deleted and express little or no new hexon proteins, input virus contain abundant hexon molecules that can be presented by dendritic cells to both CD4 and CD8 T cells. 7,20 Similarly, 'gutted' or helper-dependent Ads do not contain viral protein coding sequences but are packaged with capsid proteins. 21 Therefore, Ad-specific memory T cells from most individuals will recognize both E1-deleted and 'gutted' vectorinfected cells.…”

“…6 Moreover, in contrast to serotype-specific neutralizing antibodies, we detected Tcell responses that cross-react between serotypes. Smith et al 7 have also detected Ad-specific cytotoxic T cells (CTL) that recognize multiple serotypes.…”

Use of helper-dependent adenoviral vectors of alternative serotypes permits repeat vector administration

“…46,[59][60][61] However, a reduced persistence of expression has been observed after the second administration, 60 presumably due to cross-reacting cytotoxic T lymphocytes which can eliminate the transduced cells. 62 Over 40 different serotypes of human Ads have been isolated, suggesting that, in theory, Ad vectors of different serotypes could be administered many times throughout the life of a patient.…”

Restoration of p53 tumor-suppressor activity in human tumor cells in vitro and in their xenografts in vivo by recombinant avian adenovirus CELO-p53

“…[9][10][11] Several other mechanisms restricting the expression of Ad vectors have been reported. They include an increase of Ad-specific antibody action through the deposition of C proteins on the viral surface; 12 the development of crossreactivity of response of the CD4 þ and CD8 þ T cells to a wide range of human Ad serotypes through conservative antigens associated with class I or II MHC, 3,13,14 etc.…”