Date Published: September 30, 2019
Publisher: Public Library of Science
Author(s): Nadine Bongard, Vu Thuy Khanh Le-Trilling, Anna Malyshkina, Meike Rückborn, Kerstin Wohlgemuth, Ina Wensing, Sonja Windmann, Ulf Dittmer, Mirko Trilling, Wibke Bayer, Daniel C. Douek.
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.
In the last two decades, vector-based immunization approaches for the development of an HIV vaccine have been pursued intensively, and recently vectors based on cytomegalovirus (CMV) have drawn a lot of interest. At first glance, CMV is not an obvious choice as basis for a vaccine vector: as a β-herpes virus it carries a large and highly complex genome  that encodes numerous immune evasion proteins interfering with many aspects of immunity , and CMV infection is associated with severe illness in immune compromised or immature patients . However, after a long period of productive replication following the primary infection, CMV establishes latency from which repetitive episodes of virus reactivation can occur, leading to recurrent rounds of immunogen expression and creating a self-boosting vaccine. Furthermore, the natural CMV infection can induce inflationary T cell responses, which do not contract after the effector phase but keep expanding and can reach very high frequencies (reviewed in [4, 5]), maybe a desirable feature of vaccine-induced immunity.
CMV-based vectors have been one of the most attractive vector systems of the last years, mainly because a RhCMV-based SIV vaccine was able to confer potent protection to rhesus macaques from SIV infection. We show here that in the FV mouse model, an MCMV-based vector encoding F-MuLV Env conferred strong protection to highly FV-susceptible mice. Protection correlated strongly with the ability of the mice to mount a rapid and strong anamnestic antibody response upon challenge, but not directly with the strength of the Env-specific CD4+ T cell response, even though the cytokine profile of the Env-specific CD4+ T cells suggest that they may have some direct antiviral activity and thus contribute to control of the FV infection.