Editor’s summary
Although preclinical work in SIV- and SHIV-challenged nonhuman primates suggests that vaccine-triggered CD8+ T cells can suppress or wipe out infection, several trials of HIV vaccines known to induce CD8+ T cells have failed to show efficacy. Migueles et al. examined the functions of CD8+ T cells generated by HIV vaccines in detail to try to better understand this disconnect. They found that low-sensitivity T cell receptors (TCRs) could not properly respond to the low amounts of antigen present on HIV-infected target cells, causing impaired degranulation and low CD8+ T cell–mediated cytotoxicity. Approaches that drive further T cell clonal selection, such as administering additional vaccinations or using vaccine vectors that persist, might be one way to potentially enhance the polyclonal low-avidity CD8+ T cell responses that these HIV vaccines induce. —Seth Thomas Scanlon.
Abstract
Current HIV vaccines designed to stimulate CD8+ T cells have failed to induce immunologic control upon infection. The functions of vaccine-induced HIV-specific CD8+ T cells were investigated here in detail. Cytotoxic capacity was significantly lower than in HIV controllers and was not a consequence of low frequency or unaccumulated functional cytotoxic proteins. Low cytotoxic capacity was attributable to impaired degranulation in response to the low antigen levels present on HIV-infected targets. The vaccine-induced T cell receptor (TCR) repertoire was polyclonal and transduction of these TCRs conferred the same reduced functions. These results define a mechanism accounting for poor antiviral activity induced by these vaccines and suggest that an effective CD8+ T cell response may require a vaccination strategy that drives further TCR clonal selection.