Comprehensive analysis of virus-specific T-cells provides clues for the failure of therapeutic immunization with ALVAC-HIV vaccine

BACKGROUND: HIV-specific T-cell-based vaccines have been extensively studied in both prevention and therapeutic settings, with most studies failing to show benefit, and some suggesting harm. We previously performed a multicenter, double-blind, placebo-controlled phase II clinical trial in which 65 antiretroviral-treated patients were randomized to receive an HIV-1 recombinant canarypox vaccine (vCP1452) or placebo, followed by analytical treatment interruption. Patients exposed to vaccine had higher levels of viral replication and more rapid time to treatment resumption. OBJECTIVE: In the present study we report the results from extensive immunological investigations to test whether the preferential expansion of HIV-specific CD4(+), rather than CD8(+) T cells, could account for these unexpected results. METHODS: Polychromatic flow cytometry was used to characterize the functional and phenotypic profile of antigen-specific CD8(+) and CD4(+) T cells induced by the immunization. RESULTS: We found a significant increase in HIV-specific CD4(+) T cells producing IFN-gamma and IL-2 in the 4 injections arm compared to the placebo arm following vaccination. In contrast, no difference was observed following vaccination in the phenotype and functional capacity within the CD8(+) T-cell compartment. Neither HLA biases, nor immune hyper-activation, or Env-specific facilitating antibodies were associated with the enhanced virus rebound observed in vaccinees. CONCLUSION: Our data suggest that a vaccine-induced transient activation of HIV-specific CD4(+) but not CD8(+) T cells may have a detrimental effect on HIV outcomes. These findings may provide a mechanistic basis for higher rates of HIV acquisition or replication that have been associated with some T-cell vaccines.