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A new vaccination strategy to trigger specific CD4 T-cell response in chronic viral infection

Cellular & Molecular Immunology volume 15, pages 868–869 (2018)Cite this article

Persistent viral infections such as HIV and hepatitis C virus pose a severe health risk to the human population, which so far cannot be addressed by efficient prophylactic vaccination. Antiviral treatment is expensive and often associated with significant adverse effects. Therapeutic vaccination could therefore represent an important addition to current treatment modalities. However, vaccination of chronically infected hosts has mostly fallen short of expectations. One important reason for this is that during the development of a chronic infection, normal memory T cells do not develop.1 Instead, some specificities of virus-specific T cells are eliminated while others develop into a dysfunctional cell type termed exhausted cells. These T cells are characterized by impaired capacity for proliferation, reduced ability to secrete effector cytokines and permanent upregulation of inhibitory receptors, of which PD-1 is probably the most well known.2 Thus, based on studies in animal models like the chronic lymphocytic choriomeningitis virus (LCMV) clone 13 infection of mice, the effectiveness of therapeutic vaccination has been found to be limited by a low CD8 T-cell proliferative potential as well as a high viral load.3 However, a number studies involving the application of antibodies directed toward key immune check point inhibitors have revealed that these alone and in particular in combination with therapeutic vaccination4 may induce some measure of improved virus control in persistently infected animals. Interestingly, other ways to successfully impact virus control in chronically infected animals are treatment with exogenous IL-2(ref.5) and adoptive transfer of virus-specific CD4 T cells.6 This goes nicely in line with the fact that despite that CD8 T cells are generally central in the control of viral infections, CD4 T cells are needed to maintain CD8 T-cell activity during prolonged infection, and their role in helping the antiviral antibody response may also be essential.7 Indeed, transient depletion of CD4 T cells prior to clone 13 infection dramatically extends the course of the infection.8 In the context of treatment of chronic infection, it is important to understand that exhausted T cells are not terminally differentiated cells, they maintain some capacity to limit virus replication, and upon inhibition of PD-1/PD-L1 interaction there is a marked expansion of functional effector T cells from a subset of exhausted CD8 T cells characterized by the expression of CXCR5,9 demonstrating a potential for recovery of the antiviral immune response.

In their new study on therapeutic vaccination of mice chronically infected with LCMV clone 13, He et al.10 takes advantage of these previously established facts and put to the test whether it is possible to improve virus control in chronically infected mice by the application of vaccines initially targeting only the CD4 T cells. A heterologous prime-boost regimen was applied, which involved initial vaccination of chronically infected mice with a Listeria monocytogenes vector expressing the MHC class II-restricted GP61-80 epitope 21 days after LCMV clone 13 infection followed by systemic boosting with an influenza A (PR8) vector expressing the same epitope 7 days later. This vaccination strategy resulted in a strong, polyfunctional LCMV-specific CD4 T-cell response, which was associated with increased numbers of virus-specific CD8 T cells of normal functionality. Most importantly, substantially improved virus control was also observed. Although vaccination in itself was quite effective, combining this with blockade of the PD-1 inhibitory pathway further augmented the induced CD8 T-cell response and also significantly improved virus control in the treated animals. Notably, vaccinated mice did not become clinically affected by the treatment as it might have been expected based from the marked decline in viral load (and hence infected cells). Although there are still several things that needs to be clarified, these results are very encouraging when it comes to exploit therapeutic vaccination of chronically infected humans as an alternative or addition to pharmaceutical antiviral treatment. In fact, the study may have implications beyond virally infected patients. A dysfunctional immune response and exhausted T cells are also a common finding in cancer patients,11 and the current findings may therefore point to therapeutic vaccination targeting the CD4 T cells as a distinct possibility for treatment also in this patient group.

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References

  1. Zuniga EI, Macal M, Lewis GM, Harker JA. Innate and adaptive immune regulation during chronic viral infections. Annu Rev Virol 2015; 2: 573–597.

    Article  CAS  Google Scholar 

  2. Kahan SM, Wherry EJ, Zajac AJ. T cell exhaustion during persistent viral infections. Virology 2015; 479-480: 180–193.

    Article  CAS  Google Scholar 

  3. Wherry EJ, Blattman JN, Ahmed R. Low CD8 T-cell proliferative potential and high viral load limit the effectiveness of therapeutic vaccination. J Virol 2005; 79: 8960–8968.

    Article  CAS  Google Scholar 

  4. Ha SJ, Mueller SN, Wherry EJ, Barber DL, Aubert RD, Sharpe AH et al. Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J Exp Med 2008; 205: 543–555.

    Article  CAS  Google Scholar 

  5. West EE, Jin HT, Rasheed AU, Penaloza-Macmaster P, Ha SJ, Tan WG et al. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J Clin Invest 2013; 123: 2604–2615.

    Article  CAS  Google Scholar 

  6. Aubert RD, Kamphorst AO, Sarkar S, Vezys V, Ha SJ, Barber DL et al. Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection. Proc Natl Acad Sci USA 2011; 108: 21182–21187.

    Article  CAS  Google Scholar 

  7. Thomsen AR, Johansen J, Marker O, Christensen JP. Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice. J Immunol 1996; 157: 3074–3080.

    CAS  Google Scholar 

  8. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 1998; 188: 2205–2213.

    Article  CAS  Google Scholar 

  9. Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016; 537: 417–421.

    Article  CAS  Google Scholar 

  10. He R, Yang XX, Liu C, Chen XY, Wang L, Xiao ML et al. Efficient control of chronic LCMV infection by CD4 T cell epitope-based heterologous prime-boost vaccination in a murine model. Cell Mol Immunol 2017 (in press).

  11. Zehn D, Wherry EJ. Immune memory and exhaustion: clinically relevant lessons from the LCMV model. Adv Exp Med Biol 2015; 850: 137–152.

    Article  CAS  Google Scholar 

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  1. Department of Immunology and Microbiology, University of Copenhagen, Panum Institute, Copenhagen, DK-2200, Denmark

    Allan Randrup Thomsen

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Thomsen, A. A new vaccination strategy to trigger specific CD4 T-cell response in chronic viral infection. Cell Mol Immunol 15, 868–869 (2018). https://doi.org/10.1038/cmi.2017.19

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