Cell cycle regulation during viral infection

Abstract

To replicate their genomes in cells and generate new progeny, viruses typically require factors provided by the cells that they have infected. Subversion of the cellular machinery that controls replication of the infected host cell is a common activity of many viruses. Viruses employ different strategies to deregulate cell cycle checkpoint controls and modulate cell proliferation pathways. A number of DNA and RNA viruses encode proteins that target critical cell cycle regulators to achieve cellular conditions that are beneficial for viral replication. Many DNA viruses induce quiescent cells to enter the cell cycle; this is thought to increase pools of deoxynucleotides and thus, facilitate viral replication. In contrast, some viruses can arrest cells in a particular phase of the cell cycle that is favorable for replication of the specific virus. Cell cycle arrest may inhibit early cell death of infected cells, allow the cells to evade immune defenses, or help promote virus assembly. Although beneficial for the viral life cycle, virus-mediated alterations in normal cell cycle control mechanisms could have detrimental effects on cellular physiology and may ultimately contribute to pathologies associated with the viral infection, including cell transformation and cancer progression and maintenance. In this chapter, we summarize various strategies employed by DNA and RNA viruses to modulate the replication cycle of the virus-infected cell. When known, we describe how these virus-associated effects influence replication of the virus and contribute to diseases associated with infection by that specific virus.

Fig. 1

Overview of the eukaryotic cell cycle. The eukaryotic cell cycle consists of 4 phases; G1, S, G2, and M. Progression through the cell cycle is tightly controlled; both positive and negative regulators of the cell cycle are shown. See text and references for details

Fig. 2

Viral regulation of G0/G1 transition. Examples of viruses that can regulate the G0/G1 transition are shown. Influenza A Virus (IAV), Coronaviruses (SARS-CoA and MHV), and the Herpesvirus (EBV) encode proteins that induce a G0/G1 arrest. The mechanisms by which these viruses induce a G0/G1 arrest are shown. In contrast, some viral proteins (MT-5, encoded by the Myxoma virus and HBx, encoded by the Hepatitis B Virus (HBV)) induce progression from G0 to G1. See text and references for details

Fig. 3

Regulation of the early phases of the cell cycle by small DNA tumor viruses and the herpesviruses. Small DNA tumor viruses (Human papillomavirus (HPV), Simian virus 40 (SV40), and Adenoviruses (Ad)) and herpesviruses (Kaposi’s sarcoma-associated herpesvirus (KSHV), Epstein–Barr virus (EBV), Herpes simplex virus 1 (HSV-1), and Human cytomegalovirus (HCMV)) regulate the transition from G1 to S. The mechanism used by these viruses to regulate the early phases of the cell cycle is depicted. See text and references for details

Fig. 4

Modulation of cell proliferation pathways by HBV (HBx) and HTLV-1. The effect of HBV (HBx) on cell proliferation pathways in primary hepatocytes is depicted. Human T-cell lymphotropic virus type I (HTLV-1) encodes proteins, such as Tax and p30, which regulate cell cycle progression. See text and references for details

Fig. 5

Examples of viruses that regulate the G2/M checkpoint. Various strategies by which viruses can induce a G2/M arrest (Inactivation of the cyclin B-CDK1 complex, Cytoplasmic retention of cyclin B-CDK1 complexes, and Inhibition of mitotic exit) are depicted. The Vpr protein of human immunodeficiency virus type 1 (HIV-1) induces a G2/M arrest; some of the mechanisms by which Vpr induces a G2/M arrest are shown. See text and references for details