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Extensive cross-reactivity of adenovirus-specific cytotoxic T cells
C A Smith1, L S Woodruff, C Rooney
1Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, TN 38101, USA.
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.
Insights
Adenovirus vectors may not evade immune responses by switching serotypes due to cross-reactivity. However, cytotoxic T lymphocytes (CTLs) against one adenovirus may protect against all types, aiding immunocompromised patients.
Area of Science:
- Immunology
- Virology
- Gene Therapy
Background:
- Adenoviruses cause illness in immunocompromised individuals and are used as gene therapy vectors.
- Existing immune responses to common adenovirus serotypes (Ad2, Ad5) hinder gene therapy efficacy.
- Alternative adenovirus serotypes are proposed to bypass pre-existing immunity.
Purpose of the Study:
- To investigate the cross-reactivity of human cellular immune responses to adenoviruses.
- To determine if using uncommon adenovirus serotypes can evade memory immune responses.
Main Methods:
- Generation of human cytotoxic T lymphocytes (CTLs) in vitro against specific adenovirus serotypes.
- Testing the ability of generated CTLs to lyse cells infected with adenoviruses from different subgroups.
Main Results:
- Human CTLs generated against adenoviruses from one subgroup demonstrated cross-reactivity, lysing cells infected with adenoviruses from other subgroups.
- This cross-reactivity suggests that switching to uncommon adenovirus serotypes may not successfully evade pre-existing cellular immunity.
Conclusions:
- The proposed strategy of using uncommon adenovirus serotypes to evade memory immune responses to common serotypes may be ineffective due to cross-reactivity.
- Cross-reactivity of CTLs offers a potential therapeutic strategy: adoptive transfer of adenovirus-specific CTLs could provide broad protection against diverse adenovirus infections in immunocompromised patients.