Viral Subversion Mechanisms in Chronic Kidney Disease Pathogenesis

Leslie A. Bruggeman Department of Medicine and Rammelkamp Center for Education and Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio

Viruses cannot autonomously replicate but must rely on the host cellular machinery to support their life cycle. Through natural selection, viruses have evolved strategies to co-opt the host organism to be a better site for their propagation. Some of these strategies are directed at the cellular machinery and involve complicated and ingenious solutions to optimize infection, replication, viral gene expression, and new virion assembly and shedding. Other strategies are directed at the host’s innate and adaptive immune systems that permit the virus to evade clearance mechanisms. The more common pathogenic viral infections in nephrology—cytomegalovirus, HIV-1, hepatitis C virus, polyomavirus BK, and parvovirus B19—all have acquired subversion strategies that benefit the virus but because they interfere with normal cellular and immune processes also have become pathogenic to the host. In addition, the highly prevalent viruses cytomegalovirus, BK, and B19 cause severe disease only in the setting of immunosuppression, revealing the very delicate balance that some viruses have achieved with their host’s immune system. Thus, selective pressure for survival drives both the evolution of more sophisticated viruses and the host immune system as it evolves to combat the environment of adapting and emerging infectious agents. Understanding the molecular mechanisms of these viral subversion strategies may reveal new targets for the development of highly specific antiviral therapies and also aid vaccine development. Clin J Am Soc Nephrol 2: S13–S19, 2007. doi: 10.2215/CJN.04311206

ll viruses are obligate intracellular parasites and are ery to facilitate the first two functions. The last function is unable to replicate without the support of the cellular typically unique to each virus and because it subverts normal A machinery of the host. Because of this dependence, cellular activities is the aspect of the virus that often leads to they are at the threshold of what is considered a living organ- pathogenesis and disease. ism. For a virus to use a eukaryotic cell as a host, the virus All viruses encounter similar barriers when using a eukary- encounters many barriers to completing its life cycle and has otic cell as a host (1). The first major barrier is entering the cell, evolved mechanisms to modify the host both at the cellular and and viruses typically exploit either a receptor-mediated mech- the organismal level to ensure its survival. This article reviews anism or an endocytic process to cross the plasma membrane host–virus interactions, from the perspective of the virus, fo- (Figure 1). Once inside the cell, the virus encounters a second cusing on the more common pathogenic viruses encountered in major barrier: It must cross the nuclear membrane. Some vi- nephrology: Cytomegalovirus (CMV), HIV-1, hepatitis C virus ruses, such as parvovirus B19 (2), have evolved no specific (HCV), polyomavirus BK, and parvovirus B19. mechanism to cross the nuclear membrane. Subsequently, these Viruses are some of the smallest and simplest living or- viruses can replicate only in actively dividing cells because they ganisms, consisting of only a piece of genetic material, either must wait for the cell to enter mitosis (where the nuclear DNA or RNA, surrounded by a protein coat. All viral ge- envelope breaks down) to gain access to the critical replication nomes contain noncoding sequences that control replication and transcriptional machinery of the nucleus. After entering the and transcription, as well as coding sequences that specify nucleus, the subsequent steps of replication, transcription, the viral proteins. How many proteins each virus encodes depends mostly on the physical size of the virion, because translation of the viral genes, and assembly of new virions there are limitations on the amount of DNA or RNA that can require extensive use of the cellular machinery. The final re- be packaged within the protein coat. Viral proteins can be lease of new virions can occur by budding, commonly used by categorized into three general functions (1). The first func- the enveloped viruses such as HIV-1, which preserves the host tion is to provide for the structural proteins of the coat, the cell. Other viruses have evolved no mechanism to exit the cell second function is to ensure the replication of the genetic and either must wait for the host cell to die or, as in the case of material, and the third is to modify the host cellular machin- parvovirus B19, induce the cell to die through the expression of the viral nonstructural protein NS1, thereby releasing progeny virions on cell rupture (3). Thus, for a virus to use a cell type as Address correspondence to: Dr. Leslie Bruggeman, Rammelkamp Building a host successfully, it must accommodate any restrictions that it Room R429, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. Phone: 216-778-7603; Fax: 216-778-4321; E-mail: leslie.bruggeman@ encounters in the host cell environment or else evolve a strategy case.edu to circumvent the barriers.

Figure 1. Eukaryotic cell barriers to the viral life cycle and types of subversion mechanisms that are used by the virus. Viruses require the use of the host cellular machinery to replicate their nucleic acid and produce viral proteins for the assembly of new virion. In addition, the virus, whether intracellular and extracellular, must escape the antiviral defense mechanisms of the host’s immune system. For the virus to survive, it must evolve complex strategies to circumvent any cellular blocks to completing its life cycle and to evade the host immune system.

Subversion Mechanisms cytokine and chemokines receptors (viroreceptors), and soluble There are several subversion strategies that viruses use to cytokine-binding proteins that function as cytokine scavengers support their replication in the host cell (Figure 1). The strate- (Table 1). These viral homologues have broad-ranging effects gies are typically deployed through the use of novel, nonstruc- on lymphocyte recruitment, cytokine activation, apoptosis, and tural “accessory” proteins that either evolve de novo or are T and B cell functions, ultimately resulting in the persistence of co-opted from the host. These accessory genes will be retained a lifelong infection with periodic reactivations. in the viral genome if they provide an evolutionary selective A key immune evasion strategy of CMV is to modulate the advantage to the virus through improved viral fitness or rep- MHC I and II (6). The CMV glycoproteins US2, US3, US6, and lication capacity. However, because these accessory genes func- US11 function to downregulate posttranslationally MHC I cell tion to modify the host cell, they also frequently interfere with surface expression. US3, which is expressed in the endoplasmic normal cell functions, leading to pathogenesis (Table 1). The reticulum early in infection, also prevents the loading of pep- more common strategies include molecular mimicry, hijacking tides into MHC I and disrupts intracellular MHC II invariant host signaling pathways, and oncogenes or transforming pro- chain interactions. These viral proteins effectively function to teins to modify the cell cycle. elude effector and cytotoxic T cell responses and thus prevent the normal host response to eliminate infected cells. CMV also Molecular Mimicry Strategies produces many chemokines and chemokine receptor homo- Molecular mimicry is a strategy to imitate host proteins, and, logues that can function as either agonists or antagonists to in many instances, the viral homologues are genes that are cytokine and chemokine activity. For example, CMV produces directly pirated from the host genome through recombination an IL-10 homologue (vIL-10) that functions to suppress the events (4,5). As part of the viral life cycle, many viruses will production of other proinflammatory cytokines and the activity integrate within the host genome, and it is during these recom- of macrophages (4). Alternatively, some virokines function to bination events that host genes may be incorporated within the support virus dissemination, rather than immune evasion, by viral genome. As is typical of many of the DNA viruses, targets recruiting immune cells to the site of infection, thereby provid- for molecular mimicry are frequently immunomodulatory pro- ing additional new target cells for the virus to infect. teins directed at neutralizing the host’s antiviral measures or RNA viruses, such as the flavivirus HCV, also have proteins that preserve infected cells from death by blocking evolved intricate immune evasion strategies (Table 1). After apoptosis or cell-mediated killing activities. infection, the appearance of the HCV RNA in the cytoplasm The large ␤-herpes virus CMV is a classic example of a virus triggers the release of IFN, the key effector molecules of the that uses molecular mimicry to modify the innate, adaptive, immediate early response to viral infection (7). The HCV and inflammatory immune responses of the host. CMV pro- nonstructural (NS) protein complex NS3/4a inactivates com- duces approximately 160 proteins, and of these, only 50 to 60 ponents of the Toll-like receptor (TLR) signaling complex, are necessary for viral replication (6). The remaining 100 viral blocking the initiating mechanism of the IFN antiviral mech- proteins have evolved to manipulate the host’s immune system anism. This blockade of a key innate immune response can through mimicking host cytokines and chemokines (virokines), result in the persistence of HCV beyond the acute infection Clin J Am Soc Nephrol 2: S13–S19, 2007 Viral Subversion Mechanisms in CKD S15

Table 1. Examples of viral genes and their roles in kidney-related host pathogenesisa

No. of Viral Proteins Virus Role in Host Pathogenesis Reference Total Nonstructural, Accessoryb

B19 4 (9c) 2(4c) NS1 Cytotoxic; induces IL-6 expression (3,57) NS2 None identified BK 6 3 T antigen Blocks apoptosis, increases cell division (38) t antigen, agnoprotein None identified CMV Ϸ160 Ϸ100 Immunomodulatory (4) HCV 11 3 NS3/NS4a complex Ablates TLR3 signaling: Blocks dsRNA-induced (7,8) antiviral response NS5a Activates STAT3, increases IL-8 production; inhibits (7,8) protein kinase R: Blocks dsRNA-induced response HIV-1 15 6 Tat Mechanism unknown, possible contribution to (13,23) disease in transgenic mice Nef Hijacks Src-signaling (Stat3 and MAPK1,2 targets); (15) hijacks the cell cycle (cyclin D1 expression and retinoblastoma phosphorylation) Vpr Mechanism unknown, contributes to disease in transgenic mice Rev, Vif, Vpu None identified

aCMV, cytomegalovirus; dsRNA, double-stranded RNA; HCV, hepatitis C virus; MAPK, mitogen-activated protein kinase. bNonstructural proteins with enzymatic functions are not included. cNine unique mRNA transcripts have been identified; expression and/or function has not been determined for all putative proteins.

phase, especially in individuals with a weakened or sup- proteins within kidney cells (reviewed in references [11,12]). pressed immune system (8). Extensive work with recombinant viruses and cell culture systems (13–17) and also studies with transgenic rodents (18–25) Hijacking Strategies have shown that the expression of these accessory genes, inde- As already discussed, viruses can modify the functions of pendent of infection per se, is directly responsible for many cytokines and chemokines by producing viral homologues of aspects of HIVAN pathogenesis. In both rodent models and these key immunomodulatory host proteins. However, another infected patients, HIVAN is characterized by phenotypic strategy for viruses to accomplish the same effect is to modulate changes in epithelial cell behavior, including apoptosis, cellular the expression of the host cytokine and chemokine genes by dedifferentiation, and, most significant, excessive proliferation altering the activity of host transcription factors. This “hijack- (26). ing” of signal transduction or transcription factor activity is a As an example of a hijacking strategy in HIVAN, HIV-1 is second major subversion strategy that is used frequently by widely known to interfere with the signal transduction path- RNA viruses to manipulate the host cell (5,9). Typically, viruses way that activates the transcription factor NF-␬B (27,28). NF-␬B achieve these novel functions not by directly mimicking host protein function but through the evolution of unique accessory is the central regulator of most immune and inflammatory proteins to interact with important intracellular signaling cas- processes and controls the transcription of many host genes cades. (29). As with all viruses, the expression of the viral genes In HIV-1 infection, the virus has evolved six NS accessory depends on the available host transcription factors. HIV-1 has ␬ proteins (Table 1). The function of the accessory proteins in the evolved to exploit NF- B because it is a very potent transcrip- viral life cycle is fairly well known (10), but their role in con- tional activator in T cells and macrophages, the primary targets tributing to host pathogenesis is just beginning to emerge. In for HIV-1 infection. NF-␬B activation is controlled by phos- HIV-associated nephropathy (HIVAN), it is now accepted that phorylation and degradation of its inhibitor, I␬B, which results a part of the pathologic process is the direct infection of renal in the removal of the inhibitor from NF-␬B, allowing it to epithelia, which results in the expression of these accessory translocate to the nucleus and activate transcription. HIV-1 S16 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: S13–S19, 2007 infection of both immune cells (30,31) and kidney cells (32) velop cancer. Alternatively, it remains a possibility that the BK results in the hijacking of the NF-␬B activation process at the T antigen may be oncogenic, and BK infection could be a level of I␬B phosphorylation, inducing a persistent degradation contributing factor to urogenital and other cancers either in of I␬B and subsequent persistent activation of NF-␬B. This combination with another mutagenic event (either in the host hijacking strategy ensures that the viral genes are transcribed at cell or in the virus) or possibly in the setting of co-infection with a high rate; however, the disrupted NF-␬B activation also alters another virus, such as HIV-1 (43) or SV40 (44). the expression of many NF-␬B–dependent host genes. In HIVAN, some of these host target genes include Fas and FasL Symbiosis of Host–Virus Interactions (33) and cyclin D1 (34). The HIV-1–induced dysregulation of In the best possible scenario, the interaction of a virus with its these host genes leads to increased apoptosis and increased host is commensal, in which the virus benefits from exploiting proliferation, respectively, in renal parenchymal cells, both con- the host to ensure its own propagation but the host remains tributing processes in HIVAN pathogenesis. unharmed. The only evolutionary driving force for the virus is to replicate: To generate as many progeny virus as possible and Oncogenes and Transformation Strategies to infect as many hosts as possible. Whereas some viruses The increased proliferation of epithelial cells in HIVAN rep- establish a lifelong infection of the host while others move resents a significant difference in the pathogenic mechanism quickly from one host to the next, causing disease in the host is from the other, more common forms of FSGS, which are asso- counterproductive to the virus’s biologic success, because a sick ciated with overall loss of renal cell mass (35). This nonmalig- or dead host will only impede its ability to replicate. nant transformation of renal epithelial cells underlies both glomerular pseudocrescent and tubular cyst formation, each a Adaptation and Attenuation significant pathologic component of HIVAN. Using cell culture An example of a virulence-defeating host–virus interaction is studies, this transformation includes both increased prolifera- Ebola infection in humans (45). Although Ebola is highly trans- tion and loss of contact inhibition and seems to be caused by the missible between humans, it is also highly pathogenic, resulting function of the HIV accessory protein Nef (13) through its in almost immediate death of the host. Because Ebola is a recent hijacking of the Src-dependent signal transduction pathways infectious agent to appear in humans, the immune system has (15). Pharmaceutical suppression of this proliferative pheno- not had the evolutionary time needed to establish the symbiotic type in a transgenic mouse model of HIVAN resulted in a balance between virus and host, in which both the virus adapts significant improvement in kidney function and pathology to the host and the human immune system devises a way to (36,37). Although Nef seems to be a critical disease determinant control the new infectious agent. Over time, the biologic success in HIVAN pathogenesis, the exact causal mechanism is not of the virus (dependent on natural selection) improves in the known. Nonetheless, future therapies directed at inhibiting Nef host by both attenuation, a process whereby the virus becomes function may be useful in preventing or slowing the progres- less pathogenic, and by an increased viral replication capacity. sion of HIVAN. Studies in transgenic models have shown that Another emerging infectious disease, HIV-1, has similarly limiting the effect of HIV on the cell cycle alone through the use not had the evolutionary time to adapt and attenuate to hu- of cyclin kinase inhibitors can improve renal function and mans (46). Simian immunodeficiency virus (SIV), now accepted histopathologic changes, demonstrating that this may be a use- to be the ancestor to HIV-1, has been infecting chimpanzees for ful target for drug development (36,37). likely 10,000 yr or more (47). Within the past 100 yr, SIV made Modifying the host cell cycle and oncogenic transformation is a species jump to humans (48). A significant difference between an important survival strategy for viruses that can replicate SIV infection in chimps and HIV infection in humans is that only in actively dividing cells, such as the polyomaviruses BK, chimps do not develop AIDS and die from their infections. A JC, and SV40. Some of the most potent transforming proteins recent study showed that the viral accessory protein Nef may are the polyomavirus tumor (T) antigens. T antigens are acces- play a significant role in this difference (49). Versions of the Nef sory proteins that are required for replication of the viral DNA protein are found in HIV-1, HIV-2, and the various SIV strains, and also hijack the cell cycle by blocking the function of p53 and and it functions to remove or prevent the plasma membrane the retinoblastoma family members (38). The potency of T presentation of receptors on the cell surface. One cell surface antigens to transform cells into a state of neoplastic prolifera- receptor that is efficiently downmodulated by the SIV Nefs is tion is best characterized for the SV40 T antigen, which is CD3, which through association with the T cell receptor ini- frequently used in research applications to immortalize cell tiates activation-induced cell death, a normal and self-limiting lines for their unlimited propagation in vitro. The polyomavirus process in the homeostasis of the immune system. The HIV-1 BK, which naturally infects cells of the uroepithelium, produces Nefs in human cells do not effectively downmodulate CD3. In a small t and large T antigen (Table 1), and a possible link the setting of a chronic infection, this failure to downmodulate between BK virus infection and cancer has been proposed (39). CD3 results in robust activation-induced cell death, causing a Although it is has been shown that BK viral sequences are depletion of effector T cell populations, which subsequently present in cancers of the kidney and urinary tract, a role for the causes immunodeficiency and AIDS. SIV has adapted to the virus in oncogenesis is still debated (40–42). BK infection alone chimpanzee immune system during the past 10,000 yr to be less may not induce cancer, because BK virus infects up to 90% of pathogenic, in part by protecting the chimp’s immune system the population (39) and most infected individuals do not de- through CD3 downmodulation. Clin J Am Soc Nephrol 2: S13–S19, 2007 Viral Subversion Mechanisms in CKD S17

Balance of Host–Virus Interactions and Immunosuppression tein-1. In CMV reactivation, the immediate-early (IE) gene set It is of interest to note that the more common viral infections must be expressed to institute a new round of viral replication. related to chronic kidney disease include both viruses such as Interestingly, the CMV major immediate early promoter has HIV-1 and HCV, which have symptomatic infections and a low evolved to bind NF-␬B and activator protein-1. The normal host prevalence (2 and 0.4% respectively in the United States), and responses to an allogeneic graft induce transcription factors other viruses such as B19, BK, and CMV, which have a very that control the expression of the CMV immediate early genes, high prevalence (80 to 90% of the US population seroconvert in subsequently providing an environment to initiate a burst of childhood), and individuals typically remain asymptomatic new virus production. throughout life (50). Why does a virus that infects everyone cause disease in only a few and typically only in the setting of Conclusions immunosuppression? The obvious answer centers on the im- Viruses are incapable of autonomous replication and must munocompromised hosts and underscores the delicate balance use the available cellular machinery of the host to support their that exists between the host antiviral mechanisms and the life cycle. Because of this, viruses have evolved or borrowed ability of the virus to replicate. from the host unique survival mechanisms to permit comple- CMV is an example of a virus that has achieved a successful tion of their life cycle and include molecular mimicry, hijacking, but delicate balance between the immune system and viral and oncogenic transformation. Host pathogenesis develops escape. CMV infection causes severe disease only in the fetus or from both the host’s immune response to the infection and the newborn infants or in an immunocompromised adult, situa- disruption of the normal cell cycle and cellular functions as a tions in which the immune system is not fully functional (6). result of hijacking strategies that are used by the virus. It is Immunosuppression upsets this balance, permitting the virus survival-driven selective pressure and co-evolution of the virus to escape the clearance mechanisms of the host. In both acute with the host that shape not only the virus but also the host and (51) and likely chronic graft dysfunction (52), CMV disease its immune system. In this co-evolution, the processes of adap- primarily involves the activation of cell-mediated immunity tation and attenuation improve viral fitness as well as establish and is associated with inflammation and fibrosis in the graft. a more commensal symbiosis by making the virus less patho- As another example, B19 reactivations in immunocompro- genic to the host. Studying the adaptation and subversion mised patients (53) cause epo-resistant anemia from the direct strategies of “old” viral infections in humans may provide infection and lysis of erythroid progenitor cells, because the B19 insight into how to treat “new” infections that are highly vir- life cycle requires the death of the host cell to release new ulent and result in severe disease and mortality. virions (54). In addition, patient morbidity and graft injury result from a general, multiorgan inflammation (myocarditis, pneumonitis, hepatitis) and subsequent organ damage from Acknowledgments L.A.B. is supported by National Institutes of Health grant DK61395 scarring (55). Thus, in transplantation, the reactivations of and is an investigator in the Case Center for AIDS Research supported CMV, BK, and B19 generally result in a constant state of im- by National Institutes of Health grant AI36219. mune activation, with end organ damage occurring as a result of uncontrolled immune and inflammatory processes. Current therapies to control these reactivations have been most success- Disclosures ful with the use of specific antivirals that exploit a vulnerable None. point in the viral life cycle, such as the use ganciclovir to manage CMV infection and disease. A better understanding of References the basic biology of these different viruses and how they escape 1. 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