Mechanisms Underlying Clearance of Persistent Infections and Tumors

National Institute Of Neurological Disorders And Stroke

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Abstract

Persistent pathogens, such as human immunodeficiency virus (HIV), cause major health problems worldwide and are difficult to clear once persistence is established. Given the challenges associated with clearing persistent infections, it is important to develop and mechanistically understand therapeutic strategies that successfully achieve viral eradication without inducing permanent damage to the host. We model states of persistent infection in our laboratory using lymphocytic choriomeningitis virus (LCMV), a mouse as well as human pathogen. Persistent LCMV infections can be established by infecting mice in utero or by infecting adult mice intravenously with specific strains of the virus. When mice are persistently infected at birth or in utero with LCMV, the virus establishes systemic persistence, infecting both peripheral tissues as well as the central nervous system (CNS). Adult LCMV carrier mice are centrally tolerant to the virus at the T cell level and thus unable to eradicate the pathogen. We model persistent infection in adult mice by infecting with more aggressive strains of LCMV such as clone 13. Infection with clone 13 initiates a state of persistence that shares some important features with HIV-1 and other persistent pathogens in humans, including impairment of dendritic cells, exhaustion / deletion of the virus-specific T cells, and rapid establishment of viral persistence in the CNS as well as peripheral tissues. Both models of LCMV persistence allow us to study how the immune system can be manipulated or supplemented to control virus in the CNS and periphery. Persistent infections are often associated with functional exhaustion of pathogenic specific T cells. Exhaustion results from engagement of immunoregulatory mechanisms that are in place to protect an infected host from toxic levels of immunopathology. However, T cell exhaustion can also allow a pathogen to persist. Another challenge encountered during persistent infections is clonal deletion of T cells. Deletion is an extreme state of exhaustion resulting in the physical removal of antiviral T cells. The deleted cells often possess high avidity immunodominant T cell receptors that are among the best equipped to engage and clear infected cells. Their removal from the repertoire may reduce tissue immunopathology but render the host more vulnerable to pathogen persistence. During a chronic LCMV clone 13 infection, immunodominant nucleoprotein 396-402 specific CD8+ T cells (among others) are deleted from the repertoire within a week of infection. Importantly, we recently discovered that deletion of these potent T cells could be prevented by therapeutically administering an antiviral drug that modestly reduces viral titers. Mechanistically, we also found that preservation of this T cell population was dependent on CD4+ T cell help and interactions with costimulatory molecules (B7=1 and B7-2). Together these data demonstrate that early therapeutic reduction of viral titers can enhance virus specific CD8+ T cell diversity and function during a chronic infection. This therapeutic approach has the potential to improve long term control of persistent infections in humans. Another focus of our infectious disease research is on how tissues like the CNS return to homeostasis after a pathogen is cleared. We discovered that resolution of viral infection in the meninges is associated with peripheral immune cell engraftment. Under steady state, the meninges are inhabited by long-lived tissue resident macrophages. Upon viral infection, we observed that the meninges become heavily infiltrated by peripheral monocytes that engraft the meningeal niche and remain in situ for months after viral clearance. These cells possessed functional properties that were different than those of resident meningeal macrophages, including a loss of bacterial and immunoregulatory sensors. These data demonstrate that even clearance of an infection can imprint a tissue with new functional properties and alter its ability to respond to future challenges. Conceptually, this finding adds a new level of complexity to our understanding of how diseases can develop after a pathogen is cleared. Because the failures in adaptive immune responses to persistent infections resemble those encountered when tumors develop, our laboratory has begun studying tumor immunology to determine why the brain mounts such a poor immune response to glioblastomas. These rapidly growing tumors are uniformly fatal and impose considerable challenges on the brain resident and peripheral immune systems. We have observed that the glioblastoma microenvironment is largely silent in terms of adaptive anti-tumor immunity and instead supports an innate wound healing program that more closely resembles the response to brain injuries. Reprogramming this response so that the host views glioblastoma cells as a pathogen requires introduction of virotherapies, which have proven incredibly promising. However, even after introducing a virotherapy into the tumor microenvironment, glioblastoma cells (like other CNS residents) engage mechanisms that resist cytolytic killing by CD8+ T cells. We have observed that the CNS parenchyma (even without a tumor) prefers utilization of non-cytolytic effector mechanisms when attempting to control a pathogen. These mechanisms favor preservation of the infected CNS but give tumor cells an opportunity to grow unchecked in this compartment. We are therefore pursuing therapeutic strategies that promote uniform immune-mediated cytopathology in all glioblastoma cells.