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May 23, 2013

Using One Virus to Help the T Cells of Another

  • Scientists today report that cytomegalovirus (CMV) vectors can be genetically programmed to prod CD8+ cells into recognizing a broader range of SIV viral epitopes than they usually notice.

    In 2011, Scott Hansen, Ph.D., from Oregon Health & Sciences University, along with his colleagues reported that CMV strains engineered to express certain SIV proteins allowed vaccinated monkeys to control SIV infection.

    Writing today in Science, Dr. Hansen and his collaborators explain that the CMV 68-1 RhCMV can provoke CD8+ T cells—immune effector cells that normally respond only to MHC-1 antigens—to also respond to MHC class II (MCH-II) molecules.

    The authors point out that CD8+ T cell responses normally 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. CD8+ T cells detect intracellular pathogens by T-cell receptor (TCR)–mediated recognition of short pathogen-derived peptides, selected and transported to the cell surface by MHC-I though an intricate selection and transport process. For most pathogens, they explain,CD8+ T cell responses targeting such immunoprevalent epitopes can recognize pathogen-infected cells and mount effective antipathogen effector and memory responses.

    But, they say, efficient “immune evasion capabilities” of pathogens like SIV and HIV, allows them escape from most CD8+ T-cell immune responses.

    In their previous study, Dr. Hansen and colleagues described their HIV/AIDS vaccine strategy using an SIV protein-encoding RhCMV as a persistent vector to generate and maintain

    SIV-specific effector memory T cell responses. These responses were intended to intercept SIV infection prior to the viral amplification needed for efficient immune evasion.

    While not designed to prevent infection, they said, their strategy proved highly successful. Fifty percent of RhCMV/SIV vector–vaccinated rhesus macaques challenged with highly pathogenic SIV manifested immediate, stringent, and durable virologic control.

    During the course of these studies, the investigators noted that RhCMV/SIV vectors did not elicit the typical CD8+ T-cell responses restricted by a well characterized Rhesus macaque MHC-I allele. This led them to ask which CD8+ T-cell epitopes were targeted by these effective responses and whether differential targeting might have contributed to efficacy.

    In their the current paper, the researchers show that of SIV antigen delivery to the immune system via their novel vector fundamentally changes CD8+ T cell recognition. They further note that the SIVgag-specific CD8+ responses elicited by the RhCMV/gag vector were broader by a factor of three, and the responses targeted entirely different epitopes, including dominant MHC-II-restricted CD8+ T cell responses “rarely, if ever observed” by this class of cells to any other infectious agent.

    The authors say that these results demonstrate that CMV vectors can be genetically programmed to influence CD8+ T cells in such a way that they recognize a much broader range of SIV epitopes, and that allows them to cells mount a response that is much more robust than its usual immune response to SIV. These findings may eventually lead to more effective approaches to HIV treatment, they add.

    “Cytomegalovirus vectors violate CD8+ T Cell epitope recognition paradigms” appeared online in Science May 24.

    “Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine” was published in Nature May 26, 2011.


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