HIV-1 prime-boost vaccination shapes distinct clonal trajectories and memory precursor states of Env- and…

Abstract

Despite decades of HIV-1 vaccine development, the clonal and cellular determinants of durable vaccine-induced T cell memory remain incompletely understood. Here, we combined antigen-specific T cell receptor (TCR) identification, longitudinal TCR sequencing, and single-cell multi-omics to characterize Env- and Gag-specific memory precursor T cells elicited by the HIV Vaccine Trials Network (HVTN) 505 DNA prime-recombinant adenovirus serotype 5 (rAd5) boost (DNA/rAd5) vaccine regimen. We developed a generalizable high-throughput approach to identify HIV-1 Env- and Gag-specific TCRs and found distinct patterns of clonal expansion, persistence, and contribution to memory between Env- and Gag-specific CD8 T cell responses. The DNA prime and rAd5 boost differentially shaped these repertoires, with rAd5-induced clones contributing proportionally more to the Gag-specific than to the Env-specific memory precursor compartment. Single-cell immune profiling further revealed distinct memory precursor states, with Env-specific responses enriched for GZMBPRF1 cytotoxic effector-memory (EM) CD8 T cells and Gag-specific responses containing a larger cycling/proliferative population. Together, these findings demonstrate that heterologous DNA/rAd5 vaccination generates antigen-specific CD8 T cell memory with distinct clonal trajectories and cellular programs, providing new insights into how vaccine platform and antigen-specificity shape the durability and functional properties of HIV-1 specific cellular immunity.

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BibTeX RIS

BibTeX

@misc{xu2026hiv1,
  title = {{HIV-1 prime-boost vaccination shapes distinct clonal trajectories and memory precursor states of Env- and Gag-specific T cells}},
  author = {G. Xu and J. X. Yee and S. M. Ilcisin and S. N. Kaul and K. Mayer-Blackwell and E. Moelhman and D. R. Glass and A. A. Minervina and S. T. Karuna and M. E. Sobieszczyk and M. R. Hart and P. G. Thomas and P. J. Skene and S. C. De Rosa and M. J. McElrath and A. Fiore-Gartland and E. W. Newell},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.23.752815},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.23.752815v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - HIV-1 prime-boost vaccination shapes distinct clonal trajectories and memory precursor states of Env- and Gag-specific T cells
AU  - G. Xu
AU  - J. X. Yee
AU  - S. M. Ilcisin
AU  - S. N. Kaul
AU  - K. Mayer-Blackwell
AU  - E. Moelhman
AU  - D. R. Glass
AU  - A. A. Minervina
AU  - S. T. Karuna
AU  - M. E. Sobieszczyk
AU  - M. R. Hart
AU  - P. G. Thomas
AU  - P. J. Skene
AU  - S. C. De Rosa
AU  - M. J. McElrath
AU  - A. Fiore-Gartland
AU  - E. W. Newell
PY  - 2026
DA  - 2026/09/23
PB  - bioRxiv
DO  - 10.64898/2026.09.23.752815
UR  - https://www.biorxiv.org/content/10.64898/2026.09.23.752815v1
AB  - Despite decades of HIV-1 vaccine development, the clonal and cellular determinants of durable vaccine-induced T cell memory remain incompletely understood. Here, we combined antigen-specific T cell receptor (TCR) identification, longitudinal TCR sequencing, and single-cell multi-omics to characterize Env- and Gag-specific memory precursor T cells elicited by the HIV Vaccine Trials Network (HVTN) 505 DNA prime-recombinant adenovirus serotype 5 (rAd5) boost (DNA/rAd5) vaccine regimen. We developed a generalizable high-throughput approach to identify HIV-1 Env- and Gag-specific TCRs and found distinct patterns of clonal expansion, persistence, and contribution to memory between Env- and Gag-specific CD8 T cell responses. The DNA prime and rAd5 boost differentially shaped these repertoires, with rAd5-induced clones contributing proportionally more to the Gag-specific than to the Env-specific memory precursor compartment. Single-cell immune profiling further revealed distinct memory precursor states, with Env-specific responses enriched for GZMBPRF1 cytotoxic effector-memory (EM) CD8 T cells and Gag-specific responses containing a larger cycling/proliferative population. Together, these findings demonstrate that heterologous DNA/rAd5 vaccination generates antigen-specific CD8 T cell memory with distinct clonal trajectories and cellular programs, providing new insights into how vaccine platform and antigen-specificity shape the durability and functional properties of HIV-1 specific cellular immunity.
ER  -

Abstract

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