Abstract
Retroviral infection delivers an RNA genome into the cytoplasm that serves as the template for the synthesis of a linear double-stranded DNA copy by the viral reverse transcriptase. Within the nucleus this linear DNA gives rise to extrachromosomal circular forms, and in a key step of the life cycle is inserted into the host genome to form the integrated provirus. The unintegrated DNA forms, like those of DNAs entering cells by other means, are rapidly loaded with nucleosomes and heavily silenced by epigenetic histone modifications. This review summarizes our present understanding of the silencing machinery for the DNAs of the mouse leukemia viruses and human immunodeficiency virus type 1. We consider the potential impact of the silencing on virus replication, on the sensing of the virus by the innate immune system, and on the formation of latent proviruses. We also speculate on the changeover to high expression from the integrated proviruses in permissive cell types, and briefly consider the silencing of proviruses even after integration in embryonic stem cells and other developmentally primitive cell types.
Highlights
The introduction of foreign DNA into cells typically triggers an array of responses analogous to the sounding of alarms—the DNA is treated as a warning sign that something unusual and potentially dangerous to the cell has occurred
The system might be most important for the DNA viruses, where strong silencing might be capable of preventing infection
The potential significance of the block is perhaps reflected in the evolutionary pressure it imposes on DNA viruses, made apparent by the presence of viral genes such as the herpes virus ICP0 gene, which inactivate the silencing machinery and allow early gene expression
Summary
The introduction of foreign DNA into cells typically triggers an array of responses analogous to the sounding of alarms—the DNA is treated as a warning sign that something unusual and potentially dangerous to the cell has occurred. In a second layer of defense, any DNA that finds its way into the nucleus is subject to tight transcriptional silencing This function seems likely to have evolved to inhibit or restrict infection by viruses that would otherwise initiate a course of viral gene expression, viral replication, and potentially cell death [4]. These events have been most heavily studied in the context of infection by DNA viruses, such as the herpes viruses, but they clearly act in many diverse settings. We will speculate on the mechanisms of action of the changes that occur upon integration of the DNA into the host genome
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