HIV vaccines induce CD8 ⁺ T cells with low antigen receptor sensitivity

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.