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 2

Restricted virus-specific CD8+ T cell repertoire after vaccination and infection in INR compared with HC.

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Restricted virus-specific CD8+ T cell repertoire after vaccination and i...
(A and B) Spike-specific CD8+ T cell responses of HC (n = 11) and INR (n = 9) > 20 days after second vaccination. (A) Number of spike-specific CD8+ T cell responses to OLPs of the spike protein. Number of tested individuals (per HLA allotype and in total) and location of these epitopes within the spike protein are indicated. (B) Number of spike-specific CD8+ T cell responses per individual induced by stimulation with OLPs. (C and D) HLA-matched SARS-CoV-2–specific CD8+ T cell responses of HC (n = 10) and INR (n = 9) after vaccination and infection (hybrid immunity). (C) Percentages of SARS-CoV-2–specific CD8+ T cell responses against epitopes within the complete WT SARS-CoV-2 proteome. These CD8+ T cell epitopes have been described to be restricted by the indicated HLA allotypes. (D) Percentages of non-spike–specific CD8+ T cell responses per individual induced by stimulation with predescribed, optimal CD8+ T cell epitopes. (E) Representative dot plots of unstimulated and stimulated CD8+ T cells. Bar graph displays intracellular IFN-γ production after peptide-specific stimulation. Values are shown after subtracting the signal detected in unstimulated samples. Median values are depicted with 95% CI error bars. Statistical analysis was performed with a 2-tailed Mann-Whitney U test (B, D, and E). Circles indicate vaccine-induced CD8+ T cell responses. Triangles indicate hybrid immunity.*P < 0.05.