HIV-1 prime-boost vaccination shapes distinct clonal trajectories and memory precursor states of Env- and Gag-specific T cells
Year: 2026
Type: preprint
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 GZMB + PRF1 + 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.
Authors: Guoyue Xu, Joshua X. Yee, Saskia M. Ilcisin, Saransh N. Kaul, Koshlan Mayer-Blackwell, Ernest Moelhman, David R. Glass, Anastasia A. Minervina, Shelly T. Karuna, Magdalena E. Sobieszczyk, Matthew R. Hart, Paul G. Thomas, Peter J. Skene, Stephen C. De Rosa, M. Juliana McElrath, Andrew Fiore-Gartland, Evan W. Newell
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1305388156, G2358037835, G6714156533, G8356847483, G9000165950, HIV Vaccine Trials Network Laboratory Center, Decoding the interactions between T cell receptors and peptide-MHC, Cancer Center Support Grant, The roles of EBV-specific T cells in response to checkpoint blockade immunotherapy of EBV-driven nasopharyngeal carcinoma, Immune Responses to Malaria, HIV and SARS-CoV-2 Infection and Immunization, G9000927039
OpenAlex ID: W7214775327