Efficient control of chronic LCMV infection by a CD4 T cell epitope-based heterologous prime-boost vaccination in a...

CD4⁺ T cells are essential for sustaining CD8⁺ T cell responses during a chronic infection. The adoptive transfer of virus-specific CD4⁺ T cells has been shown to efficiently rescue exhausted CD8⁺ T cells. However, the question of whether endogenous virus-specific CD4⁺ T cell responses can be enhanced by certain vaccination strategies and subsequently reinvigorate exhausted CD8⁺ T cells remains unexplored. In this study, we developed a CD4⁺ T cell epitope-based heterologous prime-boost immunization strategy and examined the efficacy of this strategy using a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We primed chronically LCMV-infected mice with a Listeria monocytogenes vector that expressed the LCMV glycoprotein-specific I-A^b-restricted CD4⁺ T cell epitope GP61-80 (LM-GP61) and subsequently boosted the primed mice with an influenza virus A (PR8 strain) vector that expressed the same CD4⁺ T cell epitope (IAV-GP61). This heterologous prime-boost vaccination strategy elicited strong anti-viral CD4⁺ T cell responses, which further improved both the quantity and quality of the virus-specific CD8⁺ T cells and led to better control of the viral loads. The combination of this strategy and the blockade of the programmed cell death-1 (PD-1) inhibitory pathway further enhanced the anti-viral CD8⁺ T cell responses and viral clearance. Thus, a heterologous prime-boost immunization that selectively induces virus-specific CD4⁺ T cell responses in conjunction with blockade of the inhibitory pathway may represent a promising therapeutic approach to treating patients with chronic viral infections.