CD8+ T cells lacking CXCR3 and CCR5 expression have impaired contraction and generate an increased number of memory cells after virus infection.

Herpesviruses are widely disseminated in the population and establish lifelong latency, which is associated with a variety of pathological consequences. A recent report showed that mice latently infected with either murine ␥-herpesvirus-68 (␥HV68) or murine cytomegalovirus (mCMV), mouse pathogens genetically similar to the human herpesviruses, Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, and cytomegalovirus, had enhanced resistance to subsequent bacterial infection, suggesting protective as well as deleterious effects of latency. Here we confirm that latent ␥HV68 infection confers protection against subsequent infection with Listeria monocytogenes. However, the effect is transient, lasting only a few months. 67

CD4 T cells are essential for immune control of gamma-(γ)-herpesvirus latency. We previously identified a murine MHC class II-restricted epitope in γHV68 glycoprotein 150 (gp15067–83IAb) that elicits CD4 T cells that are maintained throughout long-term infection. However, it is unknown if naïve cells can be recruited into the antiviral CD4 T cell pool during latency. Here we generate a mouse transgenic for a gp150-specific T cell receptor and show epitope-specific activation of transgenic CD4 T cells during acute and latent infections. Furthermore, although only dendritic cells can stimulate virus-specific CD8 T cells during latency, we show that both dendritic cells and B cells stimulate transgenic CD4 T cells. These studies demonstrate that naïve CD4 T cells specific for a viral glycoprotein can be stimulated throughout infection, even during quiescent latency, suggesting that CD4 T cell memory is maintained in part by the continual recruitment of naïve cells.

The oncogenic γ-herpesviruses EBV and KSHV are ubiquitous human pathogens that establish lifelong latent infections maintained by intermittent viral reactivation and reinfection. Effector CD4 T cells are critical for control of viral latency and in immune therapies for virus-associated tumors. Here we exploited γHV68 infection of mice to enhance our understanding of the CD4 T cell response during γ-herpesvirus infection. Using a consensus prediction approach, we identified 16 new CD4 epitope-specific responses that arise during lytic infection. An additional epitope encoded by the M2 protein induced uniquely latency-associated CD4 T cells, which were not detected at the peak of lytic infection but only during latency, and were not induced after infection with a latency-deficient virus. M2-specific CD4 T cells were selectively cytotoxic, produced multiple antiviral cytokines, and sustained IL-2 production. Identification of latency-associated cytolytic CD4 T cells will aid in dissecting mechanisms of CD4 immune control of γ-herpesvirus latency and the development of therapeutic approaches to control viral reactivation and pathology.

The human gamma (γ)-herpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) establish lifelong latent infections, can reactivate in immunocompromised individuals, and are associated with the development of malignancies. Murine γ-herpesvirus-68 (γHV68), a rodent pathogen related to EBV and KSHV, provides an important model to dissect mechanisms of immune control and investigate vaccine strategies. Infection of mice with γHV68 elicits robust antiviral immunity, and long-term protection from γHV68 reactivation requires both cellular and humoral immune responses. Vaccination of mice with AC-RTA, a highly lytic latency-null recombinant γHV68, results in complete protection from wild-type γHV68 infection that lasts for at least 10 months. In this report, we examine the immune correlates of AC-RTA-mediated protection and show that sterilizing immunity requires both T cells and antibody. Importantly, antibody was also critical for mitigating viral infection in the brain and in the absence of antibody-mediated control, amplification of the AC-RTA virus in the brain resulted in fatality. Our results highlight important considerations in the development of vaccination strategies based on live-attenuated viruses.