Common threads in persistent viral infections

Abstract

Most viral infections are self-limiting, resulting in either clearance of the pathogen or death of the host. However, a subset of viruses can establish permanent infection and persist indefinitely within the host. Even though persisting viruses are derived from various viral families with distinct replication strategies, they all utilize common mechanisms for establishment of long-lasting infections. Here, we discuss the commonalities between persistent infections with herpes-, retro-, flavi-, arena-, and polyomaviruses that distinguish them from acutely infecting viral pathogens. These shared strategies include selection of cell subsets ideal for long-term maintenance of the viral genome, modulation of viral gene expression, viral subversion of apoptotic pathways, and avoidance of clearance by the immune system.

FIG. 1.

Selection of cell subsets ideal for long-term maintenance of the viral genome. Particular cell subsets serve as sanctuaries for the retention of a permanent viral population. Herpes simplex virus (HSV) establishes latent infection in sensory neurons. Mouse cytomegalovirus (MCMV) maintains a viral reservoir in the salivary gland. The renal epithelium is the site of permanent infection for lymphocytic choriomeningitis virus (LCMV), simian virus 40 (SV40), and JC and BK viruses. Epstein Barr Virus (EBV) resides in the memory B-cell compartment. Human immunodeficiency virus (HIV) and human T-lymphotropic virus (HTLV) persist in resting T cells. Stem cells serve as a reservoir for both mouse mammary tumor virus (MMTV) and murine leukemia virus (MuLV).

FIG. 2.

Modulation of viral gene expression. Viruses utilize reversible chromatin modifications to control transcription of viral genes. Viral transcription is active when associated with euchromatin and repressed when coupled to heterochromatin. Alternatively, host and/or viral miRNAs can be used to control production of viral proteins through translational repression or cleavage of viral mRNA. RISC, RNA-induced silencing complex.

FIG. 3.

Viral subversion of cellular apoptotic pathways. Persistent viruses must have a means to suppress apoptosis in order to maintain a compartment of infected cells. The latent proteins of EBV prevent apoptosis of infected B cells. The CMV protein vICA inhibits apoptosis by mimicking the host protein bcl-2. HCV NS5A suppresses apoptosis by inhibiting the Kv2.1 K⁺ channel, while CMV vMIA prevents caspase-8 activation. The cellular proapoptotic tumor suppressor p53 is inhibited at the transcriptional, translational, or functional level by SV40 large T antigen (LT), HCV NS3, HTLV-1 Tax, and HIV Tat. miRNAs derived from the HIV Tar transcript inhibit translation of the cellular proapoptotic proteins ERCC1, PIASγ, GIT2, and IER3.

FIG. 4.

Avoidance of clearance by the immune system. (A) Viral stimulation of IL-10 production. MMTV subverts TLR4 signaling on dendritic cells or macrophages to stimulate IL-10 production by B cells, while MCMV elicits IL-10 production by salivary gland-homed CD4⁺ T cells. LCMV stimulate dendritic cells, whereas HCV stimulates macrophages and monocytes to secrete IL-10. (B, left) Viral proteins counteract cell surface antigen presentation by MHC molecules. The HIV Tat protein inhibits transcription of MHC class I and II. Peptide loading onto MHC class I is repressed by HSV ICP47 binding to the transporter associated with antigen processing (TAP) complex. HIV Nef inhibits trafficking of MHC class I to the cell surface. HCMV proteins US2, US3, US6, and US11 target MHC class I and II for proteasomal degradation. (B, right) Inhibition of the NK cell response. Translation of the NK cell-activating ligand, MICB, is inhibited by HCMV-, KSHV-, and EBV-produced miRNAs. HIV Nef and HCV core proteins stabilize expression of HLA-C and -E, inhibitory ligands of NK receptors. CMV inhibits NK activation by expressing MHC mimics. HCV E2 binds to CD81, inhibiting its NK-activating function.