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Common Threads in Persistent Viral Infections

Melissa Kane and Tatyana Golovkina J. Virol. 2010, 84(9):4116. DOI: 10.1128/JVI.01905-09. Published Ahead of Print 2 December 2009.

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a virus may be cleared from specific cell types. Illinois 60637 Most viral infections are self-limiting. 1). suggesting that the specific architecture of the kidney may provide a particularly attractive environment for establishment of a longterm infection. For acute infections. resulting in either clearance of the pathogen or death of the host. In some instances.01905-09 Copyright © 2010. arena-. Persistence can thus be seen as a means for a virus to remain in the primary host until the opportunity to infect another organism arises. they all utilize common mechanisms for establishment of long-lasting infections. 26]). a nonproductive (latent) infection is established in nearby sensory neurons (25. 65. and/or continuous viral replication (as in the cases of flaviviruses. is able to reside within the cells of the salivary gland due to viral induction of immunosuppressive cytokine expression at this site (34) and the apparent refractive nature of the salivary gland epithelium to cytotoxic T-lymphocyte (CTL) effector functions (14). mouse cytomegalovirus (MCMV). While each virus has evolved distinct mechanisms to enable persistence. retro-. 61.uchicago. this lytic infection is subject to the actions of the immune system. These common threads linking persistent viral infections include (i) selection of cell subsets ideal for long-term maintenance of the viral genome. 1). Chicago. 57) (Fig. Specific organ anatomy can also provide a virus with the opportunity to establish a sanctuary site. 920 East 58th Street.g. 42. In the case of herpes simplex virus (HSV). E-mail: tgolovki@bsd . Many persistent infections are initiated through an acute phase of infection that provides the virus with an opportunity to establish an infection within the new host. Fax: (773) 8348150.edu. providing the virus with a virtually everlasting home within the host. which resides in the resting memory B-cell compartment (2. 70]). 72). the differentiation state of the infected cell can determine whether it is a . IL 60637. 21. Persistence can take place through nonproductive infection (e.00 doi:10. 4116 ganisms in order to be efficiently transmitted. a subset of viruses can establish permanent infection and persist indefinitely within the host. 69. 4116–4123 0022-538X/10/$12. However. 72). arenaviruses. as in the case of EpsteinBarr virus (EBV). such as the kidney in the case of lymphocytic choriomeningitis virus (LCMV). 76).. Phone: (773) 8347988. On the other hand.JOURNAL OF VIROLOGY. and these sites are cleared in immunocompetent individuals (4. The renal epithelium is also the site of persistence for several polyomaviruses. ᰔ Published ahead of print on 2 December 2009. (iii) viral subversion of cellular apoptotic pathways. Another herpesvirus. there are shared themes in the establishment and maintenance of permanent infection. 50. 35. including simian virus 40 (SV40). and polyomaviruses [11. and avoidance of clearance by the immune system. Vol. 25. while particular cell subsets serve as sanctuaries for the retention of a permanent viral population (Fig. However. Amid the daunting complexity of host-virus interactions. Department of Microbiology. All Rights Reserved. 1). these commonalities provide a point of focus for researchers hoping to treat these infections. viruses that establish persistent infections do not disseminate as easily and must often rely on close contact and direct exchange of tissues between host or* Corresponding author. the K virus of mice. flavi-. 84. Long-lived cells of the immune system can provide an ideal shelter for persistent viral infections. 25. 24. 30. and (iv) avoidance of clearance by the immune system. May 2010. No. These shared strategies include selection of cell subsets ideal for long-term maintenance of the viral genome. and the JC and BK viruses of humans (12. wherein a robust antiviral T-cell response is able to clear the virus from most organs but actually facilitates viral replication in the renal tubular epithelium (71) (Fig. SELECTION OF CELL SUBSETS FOR LONG-TERM MAINTENANCE OF THE VIRAL GENOME The first step in any viral invasion of a host is to gain access to and infect a susceptible cell. 9 MINIREVIEW Common Threads in Persistent Viral Infectionsᰔ Melissa Kane and Tatyana Golovkina* University of Chicago.1128/JVI. Subsequent to this acute phase. production of high viral titers by infected cells allows for easy dissemination and a high probability of infection of the subsequent host. In contrast. Chicago. we discuss the commonalities between persistent infections with herpes-. American Society for Microbiology. terminally differentiated cells. some viruses are able to establish persistent infections (in many cases initiated by an acute infection) through adoption of sophisticated relationships with their hosts and manipulation of a wide array of cellular mechanisms for their own advantage. 920 East 58th Street. 23. Department of Microbiology. p. Here. and polyomaviruses that distinguish them from acutely infecting viral pathogens. proviral integration into the host genome (as in the case of retroviruses [13. Most viral pathogens cause acute. (ii) modulation of viral gene expression. herpesvirus latency [21. Neurons are long-lived. productive (lytic) infection occurs in epithelial cells. viral subversion of apoptotic pathways. 72]). modulation of viral gene expression. self-limiting infections whereby the virus replicates rapidly and disseminates to another organism prior to immune clearance or the death of the host. Mailing address: University of Chicago. Even though persisting viruses are derived from various viral families with distinct replication strategies.

Epstein Barr Virus (EBV) resides in the memory B-cell compartment. One of the most well-characterized dynamic viral interactions with host chromatin proteins is that of the human T-lymphotropic virus type 1 (HTLV-1) Tax protein. 44) (Fig. while resting CD4ϩ T cells maintain a dormant reservoir of the virus (16) (Fig. Since retroviruses integrate into the host genome. 2010 MINIREVIEW 4117 bone marrow (73. An example is infection by human immunodeficiency virus (HIV). If the infected cell belongs to the stem cell population. The HSV replication cycle is cytopathic (25. a provirus may integrate into euchromatin and be expressed or integrate into heterochromatin and become repressed (59). 46). allowing for its expression (42. target for productive replication or establishment of persistence. 72) (Fig. 84. HSV latency provides an excellent example of viral interplay with host chromatin.VOL. Particular cell subsets serve as sanctuaries for the retention of a permanent viral population. simian virus 40 (SV40). less-condensed euchromatin form or the transcriptionally silent. Human immunodeficiency virus (HIV) and human T-lymphotropic virus (HTLV) persist in resting T cells. While viruses that do not use the host cell nucleus for replication cannot establish latent infections or utilize chromatin FIG. while only the latency-associated transcript (LAT) gene is associated with active euchromatin. this appears to be a virally directed process. In the host cell nucleus. 74). 1. Mouse cytomegalovirus (MCMV) maintains a viral reservoir in the salivary gland. 1). preventing their transcription. DNA is wrapped around a core of histone proteins to form the nucleosome. 42). HSV DNA exists in the nucleus in a circular episomal form associated with histones (42. cytopathic viruses need to modulate expression of their genes to ensure survival of the host cell and also to avoid immune recognition. In general. MODULATION OF VIRAL GENE EXPRESSION As already mentioned. However. Selection of cell subsets ideal for long-term maintenance of the viral genome. many cytopathic viruses utilize host mechanisms such as chromatin modification for the regulation of gene expression. Whereas some infections yield virions without causing host cell death. Retroviral proviruses are also subject to the effects of chromatin modification. patterns of persistent infections can be quite different. which infects and persists in mammary epithelial stem cells (28. as LAT gene expression alone is sufficient to promote the assembly of heterochromatin on lytic gene promoters. thus. flaviviruses). In fact. in which activated CD4ϩ T cells support productive viral replication (55). and its interactions with host chromatin-modifying enzymes are known to selectively activate or repress both viral and host genes to facilitate viral persistence (8). then the virus will persist for an indefinite period. During latent infection of neurons. provirus integrated into a silent locus may later be reactivated (59) and can thus serve as a hidden reservoir of infection. the higher-order folding of the DNA in the nucleosome results in either the transcriptionally active. and by mouse mammary tumor virus (MMTV). The site of integration is a critical factor in the level of proviral gene expression (38). and JC and BK viruses. To achieve this. Tax activity is a major factor contributing to HTLV-1 persistence. noncytopathic viruses do not need to modify their gene expression program but require attenuation of host responses to prevent clearance. The renal epithelium is the site of permanent infection for lymphocytic choriomeningitis virus (LCMV). Viruses can utilize and induce changes in chromatin structure to aid in the establishment of a persistent infection. others induce cytopathic effects in target cells. highly condensed heterochromatin form (36) (Fig. Herpes simplex virus (HSV) establishes latent infection in sensory neurons. any infected cell retains the viral genome throughout its lifetime. The need for a virus to shut down its gene expression program depends on the virus life cycle. Stem cells serve as a reservoir for both mouse mammary tumor virus (MMTV) and murine leukemia virus (MuLV). thereby limiting lytic gene expression (91). 2). establishment of a quiescent latent infection state is required for the virus to persist. This strategy is employed by retroviruses such as murine leukemia virus (MuLV). In contrast. 2). while others produce no infectious particles (herpesviruses during the latency stage). some viruses continue to replicate (arenaviruses. which establishes infection in hematopoietic progenitor cells in the . Modification of histones alters their interaction with DNA and thus influences gene expression (36). lytic genes are associated with heterochromatin. 1). providing a continuous supply of infectious virions. During this time.

a persisting virus must have a means to suppress apoptosis for a much longer time in order to maintain a compartment of infected cells (Fig. Inhibition of viral gene expression by miRNAs is not necessarily directed by the virus. the SV40 large T antigen (LT) is known to bind and inactivate p53. VIRAL SUBVERSION OF CELLULAR APOPTOTIC PATHWAYS Apoptosis is perhaps the most primordial response of a virally infected cell. whereby noncoding RNAs inhibit translation of mRNAs (15). Examples include negative regulation of the HSV type 2 (HSV-2) lytic proteins ICP34. thereby reducing CTL activation while maintaining infectious virion production (82). and -III (83.4118 MINIREVIEW J. Viral transcription is active when associated with euchromatin and repressed when coupled to heterochromatin. 2. this does not prohibit them from establishing persistent infections. HIV proviral silencing in resting CD4ϩ T cells is attributed at least in part to host miRNA-mediated suppression (33) and thus contributes to the establishment of a latent reservoir of the virus. allowing the virus to persist in cells with a specific miRNA profile. the virus must rely on its numerous immune evasion mechanisms. 3). modifications to regulate viral gene expression. which are shown to inhibit apoptosis by mimicking the host antiapoptotic protein bcl-2 and inhibiting caspase-8 activation. Other examples from the herpesvirus family include the CMV proteins vMIA and vICA. it appears that establishment of the latent reservoir is not the result of virus subversion of the immune response but rather an indirect result of host suppression of the virus. Alternatively. serving to inhibit expression of ICP0 and ICP4 (88). virus production remains high during the persistent stage of infection (65). For example. 52. This system includes the use of RNA interference. host and/or viral miRNAs can be used to control production of viral proteins through translational repression or cleavage of viral mRNA.5 and ICP0 in neurons by LAT-encoded miR-I. Whereas an acutely infecting virus needs to prevent apoptosis of infected cells only long enough to produce progeny virions. FIG. Among retroviruses. SV40 has also been shown to encode miRNAs. In this case. In addition to maintaining persistent infection by limiting viral gene transcription. VIROL. Persistent pathogens have not failed to coopt RNA interference pathways during infection. host miRNAs can also play a role in limiting viral gene expression. -II. Furthermore. The eukaryotic cell contains a complex system to regulate the expression of transcribed genes. For instance. most notably. One such example is hepatitis C virus (HCV). 2). RISC. designed to thwart the spread of infection and protect the organism as a whole. RNA-induced silencing complex. In this case. viruses often prevent translation of already-transcribed genes. respectively (27. Viruses utilize reversible chromatin modifications to control transcription of viral genes. 54). EBV latent proteins have been shown to prevent apoptosis of infected B cells. as they use both host and viral microRNAs (miRNAs) to control gene expression and promote long-term infection (Fig. The tumor suppressor protein p53 is an attractive target for many viruses. in particular that of the highly immunogenic large T antigen. 79). which accumulate later in infection and reduce expression of early viral genes. 84). the HLTV-1 Tax protein prevents apoptosis through activation of the NF-␬B and Akt cellular prosurvival pathways and neg- . The LAT of HSV-1 has also been revealed as a miRNA precursor for miR-H2-3p and miR-H6. which are discussed later and reviewed in reference 80. promoting survival of the latently infected resting B-cell compartment (31). thereby preventing apoptosis (47. Modulation of viral gene expression. which persists in the liver of most infected individuals but does not establish latency (77).

For an in-depth discussion of modulation of the immune response during persistent viral infections. Host and viral miRNAs are also utilized by persistent viruses to inhibit translation of cellular proapoptotic genes. (89). while the HIV accessory protein Tat thwarts apoptosis through inhibition of p53 transcription (29). Additionally. has recently been described (53). 93). modification of immune cell migration through chemokine mimicry by cytomegalovirus (CMV) and HIV (62). 56. GIT2. An additional novel HCV antiapoptotic mechanism wherein the viral protein NS5A inhibits the Kv2. However.1 Kϩ channel. and HIV Tat. PIAS␥. Just as the signaling networks involved in the host immune response are varied and complex. GIT2. HTLV-1 Tax transactivates promoters of the host miRNAs that target the p53 transcript. The latent proteins of EBV prevent apoptosis of infected B cells. and dysregulation of expression of cell adhesion molecules necessary for immune cell migration. viruses have evolved mechanisms in order to avoid recognition and clearance by their hosts. Thus. translational. thereby inhibiting apoptosis (7. Viral subversion of cellular apoptotic pathways. preventing hepatoma cells from apoptosis in response to oxidative stress. persistent viruses must prevent recognition and elimination by both the innate and the adaptive immune systems for long periods of time. 4A). HCV NS3.VOL. In contrast. and IER3 (41). and B-cell responses (60). IL-10 is a well-characterized immunosuppressive cytokine that inhibits a broad spectrum of immune responses. These examples are by no means exhaustive. T-cell proliferation. an in-depth discussion is beyond the scope of this review. viral evasion of the effects of these networks is also quite diverse. we will focus on the common mechanisms employed by distinct viruses to avoid immune clearance. For this reason. such as LFA-3 and ICAM-1. The cellular proapoptotic tumor suppressor p53 is inhibited at the transcriptional. and they can accomplish this through universal disruption of the immune response. the most common theme in viral subversion of immune signaling is stimulation of interleukin-10 (IL-10) production (Fig. Examples in persistent infections include inhibition of type I interferon (IFN) production by HCV (5). However. it is not surprising that successful viral infections can take advantage of IL-10 in their evasion of the immune response. HCV NS5A suppresses apoptosis by inhibiting the Kv2. The antiapoptotic HCV protein NS3 has also been shown to target p53 and inhibit its function (22). we recommend the recently published review by Virgin et al. For example. Persistent viruses must have a means to suppress apoptosis in order to maintain a compartment of infected cells. or functional level by SV40 large T antigen (LT). 68. ative regulation of p53 (85). PIAS␥. miRNAs derived from the HIV Tar transcript inhibit translation of the cellular proapoptotic proteins ERCC1. 3.1 Kϩ channel. CMV appears to exploit elevated production of IL-10 by CD4ϩ T cells homed to the . the manipulation of the apoptotic pathway is quite complex. a recent report demonstrated that miRNAs derived from the HIV-1 trans-acting responsive element (TAR) suppress the expression of several cellular genes involved in apoptosis. 84. HTLV-1 Tax. including the suppression of stimulatory cytokine production. while CMV vMIA prevents caspase-8 activation. 2010 MINIREVIEW 4119 FIG. Here. 58). and IER3. One way to avoid immune clearance is by modification of host cytokine production and signaling. Acutely infecting viruses avoid immune elimination (or death of the host) just long enough to transmit to a subsequent organism. The CMV protein vICA inhibits apoptosis by mimicking the host protein bcl-2. and for each virus. by EBV and CMV (6. including ERCC1. AVOIDANCE OF CLEARANCE BY THE IMMUNE SYSTEM Though mammals have developed an intricate and highly protective immune system. they utilize a few common strategies to manipulate the host response.

MICB. inhibiting its NK-activating function. VIROL. whereas HCV stimulates macrophages and monocytes to secrete IL-10. (B. Avoidance of clearance by the immune system. MMTV subverts TLR4 signaling on dendritic cells or macrophages to stimulate IL-10 production by B cells.4120 MINIREVIEW J. and EBV-produced miRNAs. inhibitory ligands of NK receptors. left) Viral proteins counteract cell surface antigen presentation by MHC molecules. LCMV stimulate dendritic cells. FIG. KSHV-. (B. HCMV proteins US2. The HIV Tat protein inhibits transcription of MHC class I and II. . US3. while MCMV elicits IL-10 production by salivary gland-homed CD4ϩ T cells. 4. Peptide loading onto MHC class I is repressed by HSV ICP47 binding to the transporter associated with antigen processing (TAP) complex. Translation of the NK cell-activating ligand. right) Inhibition of the NK cell response. is inhibited by HCMV-. HIV Nef inhibits trafficking of MHC class I to the cell surface. US6. HIV Nef and HCV core proteins stabilize expression of HLA-C and -E. and US11 target MHC class I and II for proteasomal degradation. HCV E2 binds to CD81. CMV inhibits NK activation by expressing MHC mimics. (A) Viral stimulation of IL-10 production.

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