Immunization with a murine cytomegalovirus based vector encoding retrovirus envelope confers strong protection from Friend retrovirus challenge infection

Abstract

Immunization vectors based on cytomegalovirus (CMV) have attracted a lot of interest in recent years because of their high efficacy in the simian immunodeficiency virus (SIV) macaque model, which has been attributed to their ability to induce strong, unusually broad, and unconventionally restricted CD8 ⁺ T cell responses. To evaluate the ability of CMV-based vectors to mediate protection by other immune mechanisms, we evaluated a mouse CMV (MCMV)-based vector encoding Friend virus (FV) envelope (Env), which lacks any known CD8 ⁺ T cell epitopes, for its protective efficacy in the FV mouse model. When we immunized highly FV-susceptible mice with the Env-encoding MCMV vector (MCMV.env), we could detect high frequencies of Env-specific CD4 ⁺ T cells after a single immunization. While the control of an early FV challenge infection was highly variable, an FV infection applied later after immunization was tightly controlled by almost all immunized mice. Protection of mice correlated with their ability to mount a robust anamnestic neutralizing antibody response upon FV infection, but Env-specific CD4 ⁺ T cells also produced appreciable levels of interferon γ. Depletion and transfer experiments underlined the important role of antibodies for control of FV infection but also showed that while no Env-specific CD8 ⁺ T cells were induced by the MCMV.env vaccine, the presence of CD8 ⁺ T cells at the time of FV challenge was required. The immunity induced by MCMV.env immunization was long-lasting, but was restricted to MCMV naïve animals. Taken together, our results demonstrate a novel mode of action of a CMV-based vaccine for anti-retrovirus immunization that confers strong protection from retrovirus challenge, which is conferred by CD4 ⁺ T cells and antibodies.

Author summary

CMV-based vectors have attracted a lot of attention in the vaccine development field, since they were shown to induce unconventionally restricted CD8 ⁺ T cell responses and strong protection in the SIV rhesus macaque model. In a mouse retrovirus model, we show now that immunization with a mouse CMV-based vector encoding retrovirus envelope conferred very strong protection, even though it was not designed to induce any CD8 ⁺ T cell responses. In this MCMV.env immunization, protection relied on the induction of CD4 ⁺ T cells and the ability to mount a strong anamnestic neutralizing antibody response upon retrovirus infection, but it was restricted to MCMV pre-naïve mice. In our model system, the MCMV based vector shows very high efficacy that is comparable to an attenuated retrovirus-based vaccine, and encourages the pursuit of this vaccination strategy.