Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan 18;11(2):211.
doi: 10.3390/vaccines11020211.

Ex Vivo Blockade of the PD-1 Pathway Improves Recall IFNγ Responses of HIV-Infected Persons on Antiretroviral Therapy

Natalie Fischhaber  1 , Moritz Schmiedeberg  1 , Sabrina Kübel  1 , Ellen G Harrer  2 , Thomas Harrer  2 , Krystelle Nganou-Makamdop  1
Affiliations

Ex Vivo Blockade of the PD-1 Pathway Improves Recall IFNγ Responses of HIV-Infected Persons on Antiretroviral Therapy

Natalie Fischhaber et al. Vaccines (Basel). .

Abstract

Despite antiretroviral therapy (ART), immune exhaustion persists in HIV infection and limits T cell responses to HIV or other pathogens. Moreover, HIV infection results in the loss of pre-existing immunity. Here, we investigated the effect of blocking the PD-1 pathway on recall IFNγ responses to tetanus toxoid (TT) and measles virus (MV) antigens in HIV-infected persons on ART with prior TT and MV immunity. The ex vivo treatment of lymphocytes with anti-PD-1 and anti-PD-L1 antibodies significantly increased TT- and MV-specific IFNγ responses. The responses to TT and MV antigens alone or in combination with antibodies blocking the PD-1 pathway positively correlated with CD4 T cell levels. Furthermore, T cell PD-1 expression levels inversely correlated with recall IFNγ responses in combination with antibodies blocking the PD-1 pathway but not with IFNγ responses to antigens only. Our study suggested that targeting the PD-1 pathway may boost vaccine-induced pre-existing immunity in HIV-infected persons on ART depending on the degree of immune exhaustion.

Keywords: HIV infection; PD-1 pathway; T cell exhaustion; anti-PD-1; anti-PD-L1; vaccine-induced immunity.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
TT-specific IFNγ responses and antibody levels among the HIV-infected and HIV-uninfected study participants. (a) IFNγ concentrations in the supernatant 3 days after stimulation with TT protein in persons with self-reported prior vaccination. Background responses (unstimulated condition) are subtracted for each participant. (b) Plasma levels of the anti-TT IgG antibodies in persons with self-reported prior vaccination. Medians, interquartile ranges and p-values of the comparison between groups using the Mann–Whitney test are presented.
Figure 2
Figure 2
IFNγ responses upon ex vivo blockades of the PD-1 pathway. (a) TT-specific IFNγ responses of the HIV-infected TT-seropositive persons upon the addition of anti-PD-1 or anti-PD-L1 antibodies at concentrations of 20 or 40 µg/mL. (b) TT-specific IFNγ responses of a separate set of the HIV-infected TT-seropositive persons upon the addition of anti-PD-L1 (20 and 40 µg/mL) or anti-PD-1 (40 µg/mL) and their respective isotype controls, namely, human IgG1 and human IgG4. (c) MV-specific IFNγ responses of the HIV-infected MV-seropositive persons upon the addition of anti-PD-L1 at concentrations of 20 or 40 µg/mL. (d) MV-specific IFNγ responses of a separate set of HIV-infected MV-seropositive persons upon the addition of anti-PD-L1 (20 and 40 µg/mL) or anti-PD-1 (40 µg/mL) and their respective isotype controls human IgG1 and human IgG4. The background responses (unstimulated condition) were subtracted for each participant. Medians, interquartile ranges and p-values of the comparison between stimulation conditions using the Wilcoxon test are presented.
Figure 3
Figure 3
Correlation between the blood CD4 T cell levels and T cell PD-1 expression levels. (a) Linear regression analysis with percentages of CD4 T cells. (b) Linear regression analysis with CD4 T cell counts (cells/µL). The 95% confidence interval of linear regression, as well as the rhos and p-values of the Spearman correlations, are presented.
Figure 4
Figure 4
Association between the T cell PD-1 expression levels and TT-specific IFNγ responses in the presence of antibodies blocking the PD-1 pathway. (a) T cell PD-1 expression levels of the participants with upper or lower quartiles of IFNγ responses to TT alone, TT+ anti-PD-L1 (20 µg/mL) or TT+ anti-PD-1 (40 µg/mL). Medians, interquartile ranges and p-values of the comparison between groups using the Mann–Whitney test are presented. (b) Correlation analysis between the T cell PD-1 expression levels and IFNγ responses to TT+ anti-PD-L1 (20 µg/mL) of the 30 TT-seropositive HIV-infected persons. (c) Correlation analysis between the T cell PD-1 expression levels and IFNγ responses to TT+ anti-PD-1 (40 µg/mL). The 95% confidence interval of the linear regression, as well as the rhos and p-values of the Spearman correlations, are presented.
Figure 5
Figure 5
Association between the T cell PD-1 expression levels and MV-specific IFNγ responses in the presence of antibodies blocking the PD-1 pathway. (a) T cell PD-1 expression levels of the participants with upper or lower quartiles of IFNγ responses to MV alone, MV+ anti-PD-L1 (20 µg/mL) or MV+ anti-PD-L1 (40 µg/mL). Medians, interquartile ranges and p-values of the comparison between groups using the Mann–Whitney test are presented. (b) Correlation analysis between the T cell PD-1 expression levels and IFNγ responses to TT+ anti-PD-L1 (40 µg/mL) of the 29 MV-seropositive HIV-infected persons. The 95% confidence interval of the linear regression, as well as the rhos and p-value of the Spearman correlations, are presented.
See this image and copyright information in PMC

References

    1. Wherry E.J. T Cell Exhaustion. Nat. Immunol. 2011;12:492–499. doi: 10.1038/ni.2035. - DOI - PubMed
    1. Crawford A., Angelosanto J.M., Kao C., Doering T.A., Odorizzi P.M., Barnett B.E., Wherry E.J. Molecular and Transcriptional Basis of Cd4(+) T Cell Dysfunction During Chronic Infection. Immunity. 2014;40:289–302. doi: 10.1016/j.immuni.2014.01.005. - DOI - PMC - PubMed
    1. D’Souza M., Fontenot A.P., Mack D.G., Lozupone C., Dillon S., Meditz A., Wilson C.C., Connick E., Palmer B.E. Programmed Death 1 Expression on Hiv-Specific Cd4+ T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction. J. Immunol. 2007;179:1979–1987. doi: 10.4049/jimmunol.179.3.1979. - DOI - PubMed
    1. Day C.L., Kaufmann D.E., Kiepiela P., Brown J.A., Moodley E.S., Reddy S., Mackey E.W., Miller J.D., Leslie A.J., DePierres C., et al. Pd-1 Expression on Hiv-Specific T Cells Is Associated with T-Cell Exhaustion and Disease Progression. Nature. 2006;443:350–354. doi: 10.1038/nature05115. - DOI - PubMed
    1. Haase A.T., Henry K., Zupancic M., Sedgewick G., Faust R.A., Melroe H., Cavert W., Gebhard K., Staskus K., Zhang Z.Q., et al. Quantitative Image Analysis of Hiv-1 Infection in Lymphoid Tissue. Science. 1996;274:985–989. doi: 10.1126/science.274.5289.985. - DOI - PubMed