HIV-1 prime-boost vaccination shapes distinct clonal trajectories and memory precursor states of Env- and Gag-specific T cells

For decades, researchers have struggled to understand the clonal and cellular factors that lead to long-lasting T cell memory induced by HIV-1 vaccines. In a recent study, scientists combined advanced T cell receptor identification, longitudinal sequencing, and single-cell multi-omics to analyze the memory precursor T cells generated by the HIV Vaccine Trials Network 505 DNA prime-recombinant adenovirus serotype 5 (rAd5) booster vaccine (DNA/rAd5).

By developing a scalable, high-throughput method to detect HIV-1 Env- and Gag-specific TCRs, the researchers identified unique patterns in the expansion, survival, and impact on memory between Env- and Gag-specific CD8 T cell responses. The DNA prime and rAd5 boost sequences produced different outcomes for these cell populations, with rAd5-specific clones making up a larger proportion of Gag-specific memory precursors compared to the Env-specific response.

Further single-cell analysis revealed separate memory precursor states, with Env-specific responses having a higher proportion of cytotoxic effector-memory (EM) CD8 T cells and Gag-specific responses featuring a greater number of cycling/proliferative cells. In summary, this research reveals that the heterologous DNA/rAd5 vaccine regimen creates distinct clonal trajectories and cellular programs in the immune system, offering fresh insights into how vaccine platform and antigen specificity affect the long-term durability and functional characteristics of HIV-1-specific cellular immunity.