Limited vaccine-induced CD8+ T cell immunity in HIV-infected immunological nonresponders
Vivien Karl, Anne Graeser, Anastasia Kremser, Liane Bauersfeld, Florian Emmerich, Nadine Herkt, Siegbert Rieg, Susanne Usadel, Bertram Bengsch, Tobias Boettler, Hendrik Luxenburger, Christoph Neumann-Haefelin, Matthias C. Müller, Robert Thimme, Maike Hofmann
Vivien Karl, Anne Graeser, Anastasia Kremser, Liane Bauersfeld, Florian Emmerich, Nadine Herkt, Siegbert Rieg, Susanne Usadel, Bertram Bengsch, Tobias Boettler, Hendrik Luxenburger, Christoph Neumann-Haefelin, Matthias C. Müller, Robert Thimme, Maike Hofmann
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Clinical Research and Public Health AIDS/HIV Immunology Virology

Limited vaccine-induced CD8+ T cell immunity in HIV-infected immunological nonresponders

Abstract

BACKGROUND Among people living with HIV (PLWH), immunological nonresponders (INR) fail to adequately restore CD4+ T cell counts despite effective antiretroviral therapy (ART), placing them at greater risk for adverse outcomes and reduced vaccine efficacy. We aimed to study the robustness and longevity of vaccine-induced virus-specific cellular immune responses in INR.METHODS Virus-specific CD8+ T cell responses were analyzed in INR (CD4+ T cell count < 300 cells/μL) and immunological responders (IR) (CD4+ T cell count > 500 cells/μL), receiving ART, and HIV-uninfected controls following COVID-19 mRNA vaccination and infection. Virus-specific CD8+ T cells were characterized using peptide-loaded MHC I tetramer technology, after in vitro expansion and cytokine production assays. Virus-specific CD4+ T cells and IgG levels were determined by activation-induced marker (AIM) assay and ELISA, respectively.RESULTS We demonstrated that, while long-lasting virus-specific cellular immune responses were generated in INR, CD8+ T cell immunity remained limited compared with robust CD4+ T cell reactivity. CD8+ T cell responses in INR exhibited reduced breadth and frequency, accompanied by altered memory differentiation and suboptimal activation and effector response upon antigen exposure. This deficiency correlated with low CD4+ T cell counts, independent of other disease markers, highlighting the pivotal role of CD4+ T cells in orchestrating vaccine-induced immunity. Notably, repeated booster vaccinations enhanced virus-specific CD8+ T cell responses.CONCLUSION INR elicit limited vaccine-induced virus-specific CD8+ T cell immunity, but booster vaccinations can enhance these responses, suggesting better immune outcomes with tailored vaccination strategies.FUNDING Helmholtz Society, German Research Foundation, Federal Ministry of Education and Research.

Authors

Vivien Karl, Anne Graeser, Anastasia Kremser, Liane Bauersfeld, Florian Emmerich, Nadine Herkt, Siegbert Rieg, Susanne Usadel, Bertram Bengsch, Tobias Boettler, Hendrik Luxenburger, Christoph Neumann-Haefelin, Matthias C. Müller, Robert Thimme, Maike Hofmann

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Figure 3

Reduced spike-specific CD8+ T cell memory formation in INR compared with HC.

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Reduced spike-specific CD8+ T cell memory formation in INR compared with...
(A) Calculated ex vivo frequencies of spike-specific CD8+ T cells in HC (n = 24) and INR (n = 12) > 90 days after second (gray; green) or third (white; dark green) mRNA vaccination. (B–D) Percentages and calculated ex vivo frequencies of CD127+ (HC n = 24; INR n = 10) (B), BCL-2hi (HC n = 24; INR n = 10) (C), and TCF-1+ (HC n = 24; INR n = 9) (D) nonnaive spike-specific CD8+ T cells. (E) Percentages of spike-specific CD8+ T cell memory subsets in HC (n = 24) and INR (n = 10). TEMRA, terminally differentiated effector memory cells reexpressing CD45RA; TEM, effector memory; TTM, transitional memory; TCM, central memory; TSCM, stem cell–like memory. (F) t-SNE representation of flow cytometry data depicting spike-specific CD8+ T cells > 90 days after second and third mRNA vaccination. Gray, HC after first boost (n = 17) and after second boost (n = 6); green, INR post first boost (n = 7) and after second boost (n = 2). (G) Calculated ex vivo frequencies of spike-specific CD8+ T cell memory subsets in HC (n = 24) and INR (n = 10). Gray and green indicate time points post second vaccination. White and dark green indicate time points post third vaccination. Median values are depicted with 95% CI error bars. Statistical analysis was performed with a 2-tailed Mann-Whitney U test (A–D and G). Circles indicate vaccine-induced CD8+ T cell responses. Triangles indicate hybrid immunity. *P < 0.05, **P < 0.01, ***P < 0.001.