The many millions of humans who have life-long virus infections represent a major health issue for the 21st century but also a unique opportunity for investigative virologists. For persistent virus infections to endure, two ingredients are essential. The first is a unique strategy of viral replication; that is, instead of killing its host cell, the pathogen causes little to no damage so it can continue to reside in those cells. The second requirement for persistent virus infection is an immune response that does not react to or remove virus-infected cells. Overall, our knowledge of how viral genes and cellular factors interact to allow persistence to occur is incomplete. Although our libraries contain volumes of facts on this subject, many physiologic functions and interrelationships of viral genes with host genes that establish persistence remain, in large part, unknown.
We do know that acutely infected cells express viral peptides, which, when attached to host major histocompatibility complex (MHC) molecules on their surfaces, signal the immune system to kill such cells. However, viruses apply numerous avoidance strategies to persist. One is direct selective pressure to suppress the infected host’s innate and/or adoptive immune system that would otherwise destroy them. For example, viruses can alter or interfere with the processing of viral peptides by professional antigen-presenting cells, thereby restricting expression of MHC/peptide complexes on cell surfaces, a requirement for activation and expansion of the T cells that normally remove infected cells. Additionally, viruses can downregulate co-stimulatory and/or MHC molecules also required for T cell signaling and expansion; they can inhibit the differentiation of antigen-presenting conventional dendritic cells (cDCs), and can infect effector T and B cells directly. Similarly, to persist in infected cells, viruses can disrupt the processing or migration of viral peptides or viral peptide/MHC complexes to the cells’ surface, thereby removing the recognition signals for activated killer T cells. Finally, viruses that persist frequently infect neurons, which have defects in TAP, a molecule required for the translocation of viral peptides to endoplasmic reticulum (ER). Perhaps neurons can also actively prevent cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells from degranulating and thereby limit the activity of such virus-removing effector cells. Since neurons are essential to health but rarely regenerate when destroyed, Darwinian selection likely caused them to evolve mechanisms to avoid immunologic assault. Such events would allow infected neurons to escape immune recognition and live, as well as allow viruses to persist in a neuronal safe house.
Currently researchers are engaged in the discovery of additional negative immune regulators and their signaling pathway(s) using gene chip and forward genetics technology. These projects have a multitude of applications. Some examples are the development of pharmacologic small molecules as effective antagonists of negative immune regulators, the use of transient negative regulator blockers as an adjuvant approach to enhance both prophylactic and therapeutic vaccination, and the determination of how long during the course of persistent virus infection exhausted T cells can be rescued to become antiviral effector T cells. As always, the goal is to understand basic principles in viral pathogenesis and to extend results in the murine model to resolve persistent infections of humans.
Anatomy of Viral Persistence. PLoS Pathog 5(7): e1000523 doi:10.1371/journal.ppat.1000523
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