Extensive Cross-Reactivity of Adenovirus-Specific Cytotoxic T Cells

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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 is one of two major viral vectors used in clinical gene therapy protocols, but to date the findings have been somewhat disappointing. A preexisting immune response to the viral protein, accompanied in some cases by a de novo response to the transgene, limit the level and time of expression of the therapeutic transgene. To overcome this problem it has been suggested that alternative adenovirus serotypes, for which previous exposure is less likely, might be used. This is based on the low levels, and lack of neutralizing activity, of cross-subgroup-reactive antibodies. Our data indicate that the cellular immune response to Ad5 generates highly cross-reactive cytotoxic T cells capable of lysing cells infected with adenoviruses from other subgroups. While indicating that the use of vectors from other subgroups may not be successful, the results do indicate that in vitro-generated CTLs against Ad5 could protect immunosuppressed patients from infections by all subgroups.