Journal Article

Cytomegalovirus Vectors Violate CD8⁺ T Cell Epitope Recognition Paradigms

Lifson, Jeffrey D., Ford, Julia C., Picker, Louis J., Früh, Klaus, Gilliam, Awbrey N., Ventura, Abigail B., Edlefsen, Paul T., Hammond, Katherine B., Lewis, Matthew S., Scholz, Isabel, Xu, Guangwu, Turner, John M., Axthelm, Michael K., Nelson, Jay A., Richards, Rebecca, Sacha, Jonah B., Legasse, Alfred W., Hansen, Scott G., Hughes, Colette M., Gilbride, Roxanne M., Burwitz, Benjamin J., Whizin, Nathan, Reed, Jason S., Malouli, Daniel, Fischer, Miranda

2013

Overview

One vaccine strategy being pursued against HIV is to generate protection that is dependent on cell-mediated, rather than humoral, immune responses. A cytomegalovirus (CMV)–vectored vaccine that expresses simian immunodeficiency virus (SIV) antigens exhibits stringent and durable viral control upon SIV challenge in approximately half of vaccinated rhesus macaques. Hansen et al. ( 10.1126/science.1237874 , see the Perspective by Goonetilleke and McMichael ) sought to determine the basis for the protection and discovered that the CD8 + T cell response in vaccinated monkeys does not target canonical SIV epitopes, which SIV is known to escape, but rather generates a broad, promiscuous response. A vaccine that uses one virus to deliver components of a second virus elicits T cells that recognize noncanonical epitopes. [Also see Perspective by Goonetilleke and McMichael ] CD8 + T cell responses focus on a small fraction of pathogen- or vaccine-encoded peptides, and for some pathogens, these restricted recognition hierarchies limit the effectiveness of antipathogen immunity. We found that simian immunodeficiency virus (SIV) protein–expressing rhesus cytomegalovirus (RhCMV) vectors elicit SIV-specific CD8 + T cells that recognize unusual, diverse, and highly promiscuous epitopes, including dominant responses to epitopes restricted by class II major histocompatibility complex (MHC) molecules. Induction of canonical SIV epitope–specific CD8 + T cell responses is suppressed by the RhCMV-encoded Rh189 gene (corresponding to human CMV US11 ), and the promiscuous MHC class I– and class II–restricted CD8 + T cell responses occur only in the absence of the Rh157.5 , Rh157.4 , and Rh157.6 (human CMV UL128 , UL130 , and UL131 ) genes. Thus, CMV vectors can be genetically programmed to achieve distinct patterns of CD8 + T cell epitope recognition.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Animals / CD8-positive T-lymphocytes / CD8-Positive T-Lymphocytes - immunology / cell-mediated immunity / Cytokines - immunology / Cytomegalovirus / Cytomegalovirus - genetics / Cytomegalovirus - immunology / Epitopes / Epitopes, T-Lymphocyte - immunology / exhibitions / Feedback (Response) / Female / genetic vectors / Genetic Vectors - genetics / Genetic Vectors - immunology / Histocompatibility Antigens Class II - immunology / Human immunodeficiency virus / Humans / immune response / Infections / Logical Thinking / Macaca mulatta / Male / Membrane Glycoproteins - genetics / monkeys / Pathogens / Peptides / RESEARCH ARTICLE SUMMARY / SAIDS Vaccines - administration & dosage / SAIDS Vaccines - immunology / Simian immunodeficiency virus / T lymphocytes / Vaccination / Vaccines / Viral Envelope Proteins - genetics