Figure 2 - uploaded by Timothy Baszler
Content may be subject to copyright.
Immunoperoxidase staining ofthe brainstem at day 15 after inoculation using anti-MoMuLVantibody: Viral immunostaining of capillary endothelia (large arrowheads) and mild vasocentric neuronal swelling and neuropil spongiosis. Occasional viral immunostaining of microglia (small arrowheads). No viral immunostaining of neurons (hematoxylin counterstain, X300).
Source publication
To determine the biologic basis of ts1 MoMuLV neurovirulence in vivo, newborn CFW/D mice were inoculated with neurovirulent ts1 MoMuLV and nonneurovirulent wt MoMuLV and the temporal response to virus infection in the central nervous system (CNS), spleen, and thymus was studied comparatively. Experimental procedures included single and double label...
Contexts in source publication
Context 1
... Immunohistochemistry Virus infection of the CNS occurred subsequent to infection of both the spleen and thymus. Both viral gag and env antisera labeled virus-infected neural cells equally. The degree of viral antigen accumulation and the sequence of virus infection were identical in both tsl and wt MoMuLV-infected mice until day 20 after inoculation. During this early period of virus infection, cellular targets for virus infection (first detected on day 15 after inocula- tion) were capillary endothelial cells and occasional mi- croglia within targeted areas of the brainstem and spinal cord (Figure 2). Early virus infection of CNS capillary en- dothelial cells was temporally and spatially correlated with mild, local, vasocentric spongiform lesions and neu- ronal swelling in both wt and tsl MoMuLV-infected mice (Figure 2), but infection of endothelial cells was not asso- ciated with neurologic disease. Direct virus infection of neurons was not observed during the inception of early neuronal degeneration. There was occasional viral anti- gen immunostaining of capillary endothelial cells and Bergman's glial cells in the cerebellum; these areas of the CNS never developed spongiform ...
Context 2
... Immunohistochemistry Virus infection of the CNS occurred subsequent to infection of both the spleen and thymus. Both viral gag and env antisera labeled virus-infected neural cells equally. The degree of viral antigen accumulation and the sequence of virus infection were identical in both tsl and wt MoMuLV-infected mice until day 20 after inoculation. During this early period of virus infection, cellular targets for virus infection (first detected on day 15 after inocula- tion) were capillary endothelial cells and occasional mi- croglia within targeted areas of the brainstem and spinal cord (Figure 2). Early virus infection of CNS capillary en- dothelial cells was temporally and spatially correlated with mild, local, vasocentric spongiform lesions and neu- ronal swelling in both wt and tsl MoMuLV-infected mice (Figure 2), but infection of endothelial cells was not asso- ciated with neurologic disease. Direct virus infection of neurons was not observed during the inception of early neuronal degeneration. There was occasional viral anti- gen immunostaining of capillary endothelial cells and Bergman's glial cells in the cerebellum; these areas of the CNS never developed spongiform ...
Citations
... Moreover, specific viral clones have been characterized that are capable of causing rapid, progressive, paralytic diseases accompanied by non-inflammatory spongiform neuropathology reminiscent of prion diseases (Gardner et al., 1973;Gardner, 1978Gardner, , 1985. Prior research has identified many different CNS cell types as being infected by both neurovirulent and non-neurovirulent MLVs (Baszler and Zachary, 1991;Lynch et al., 1991;Gravel et al., 1993;Lynch and Portis, 1993;Robertson et al., 1997), but it is unknown which, if any of these cells is responsible for the altered neurophysiology and clinical neurological changes arising in infected mice (Li et al., 2014). While postnatally proliferating neurons are MLV targets, they do not undergo neurodegenerative changes (Lynch et al., 1991;Gravel et al., 1993). ...
The ability of retroviruses (RVs) to cause neurodegeneration is critically dependent upon two activities of the envelope protein (Env). First, Env facilitates viral genome delivery to CNS target cells through receptor binding and membrane fusion. Second, Env expression within one or more targets indirectly alters the physiology of certain neurons. Although the major Env expressing CNS cell types have been identified for many neurovirulent RVs, it remains unresolved, which targets play a causal role in neuropathogenesis. Moreover, this issue is complicated by the potential for post-infection virus suppression. To address these questions we explored herein, whether and how cryptic neurotropism differences between ecotropic and amphotropic murine leukemia viruses (MLVs) impacted neurovirulence. Neurotropism was first explored ex vivo using (1) acute primary glial cell cultures and (2) neural progenitor cell (NPC)- neural stem cell (NSC) neural sphere (NPH) chimeras. These experiments indicated that primary astrocytes and NPCs acutely restrict amphotropic but not ecotropic virus entry. CNS tropism was investigated using NSC transplant-based Cre-vector pseudotyping wherein mTmG transgenic fluorescent protein reporter mice revealed both productive and suppressed infection. Cre-pseudotyping with FrCasE, a prototypic neurovirulent ecotropic virus, identified glia and endothelia, but not neurons, as targets. Almost two-thirds (62%) of mGFP+ cells failed to show Env expression, suggesting widespread virus suppression. To circumvent RV superinfection interference confounds, targets were also identified using ecotropic packaging NSCs. These experiments identified known ecotropic targets: microglia, oligodendrocyte progenitor cells (OPCs) and endothelia. Additionally, one third of mGFP+ cells were identified as protoplasmic astrocytes, cells that rarely express virus in vivo. A CNS targeting comparison between isogenic ecotropic (FrCasE) and amphotropic (FrAmE) viruses showed a fourfold higher astrocyte targeting by FrCasE. Since ecotropic Env pseudotyping of amphotropic virus in the CNS dramatically exacerbates neurodegeneration, these results strongly suggest that astrocyte infection is a major disease requirement. Moreover, since viral Env protein expression is largely subdetectable in astrocytes, minimal viral protein expression appears sufficient for affecting neuronal physiology. More broadly, these findings raise the specter that subdetectable astrocyte expression of exogenous or endogenous RVs could play a major role in human and animal neurodegenerative diseases.
... MLVs infect many different CNS cell types, including postnatally proliferating neurons, neuroglia, microglia, and vascular endothelial cells; however, the postmitotic neurons that undergo degenerative changes appear refractory to infection. NVs and nonneurovirulent MLVs (NNs) with the same host range show no CNS cellular-tropism differences (14,(20)(21)(22), indicating that neurodegeneration results from the expression of unique neurovirulent Env conformers within one or more neuronal support cells. The questions of which neural cells are important and how they alter neuronal function remain largely unresolved. ...
Importance:
A variety of human and animal retroviruses are capable of causing central nervous system (CNS) neurodegeneration manifest as motor and cognitive deficits. These retroviruses infect a variety of CNS cell types, however, the specific role each cell type plays in neuropathogenesis remains to be established. The NG2 glia, whose CNS functions are only now emerging, are a newly appreciated viral target in murine leukemia virus (MLV)-induced neurodegeneration. Since one role of NG2 glia is that of oligodendrocyte progenitor cell (OPC), we investigated here whether their infection by the neurovirulent MLV, FrCasE, contributed to neurodegeneration by affecting OPC viability and/or development. Our results show that both neurovirulent and non-neurovirulent MLVs interfere with oligodendrocyte differentiation. Thus, NG2 glial infection could contribute to neurodegeneration by preventing myelin formation and/or repair, and by suspending OPCs in a state of persistent susceptibility to excitotoxic insult mediated by neurovirulent virus affects on other glial subtypes.
... Infection of CNS glia most closely correlates with the appearance of degenerative changes (Baszler and Zachary 1991;Clase et al. 2006;Hansen et al. 2000;Kay et al. 1991;Lynch et al. 1991;Morey and Wiley 1990;Robertson et al. 1997); however, which glial subtype(s) is/are involved and their pathogenic mechanism(s) remain unclear (cf. Li et al. 2011). ...
Certain retroviruses induce progressive spongiform motor neuron disease with features resembling prion diseases and amyotrophic lateral sclerosis. With the neurovirulent murine leukemia virus (MLV) FrCasE, Env protein expression within glia leads to postsynaptic vacuolation, cellular effacement, and neuronal loss in the absence of neuroinflammation. To understand the physiological changes associated with MLV-induced spongiosis, and its neuronal specificity, we employed patch-clamp recordings and voltage-sensitive dye imaging in brain slices of the mouse inferior colliculus (IC), a midbrain nucleus that undergoes extensive spongiosis. IC neurons characterized by postinhibitory rebound firing (PIR) were selectively affected in FrCasE-infected mice. Coincident with Env expression in microglia and in glia characterized by NG2 proteoglycan expression (NG2 cells), rebound neurons (RNs) lost PIR, became hyperexcitable, and were reduced in number. PIR loss and hyperexcitability were reversed by raising internal calcium buffer concentrations in RNs. PIR-initiated rhythmic circuits were disrupted, and spontaneous synchronized bursting and prolonged depolarizations were widespread. Other IC neuron cell types and circuits within the same degenerative environment were unaffected. Antagonists of NMDA and/or AMPA receptors reduced burst firing in the IC but did not affect prolonged depolarizations. Antagonists of L-type calcium channels abolished both bursts and slow depolarizations. IC infection by the nonneurovirulent isogenic virus Friend 57E (Fr57E), whose Env protein is structurally similar to FrCasE, showed no RN hyperactivity or cell loss; however, PIR latency increased. These findings suggest that spongiform neurodegeneration arises from the unique excitability of RNs, their local regulation by glia, and the disruption of this relationship by glial expression of abnormal protein.
... Productive virus infection of other neuron populations has been reported for brain areas where neuronal progenitor cells proliferate postnatally (i.e., the cerebellar cortex, the olfactory bulb, and the hippocampal dentate gyrus); however, these neurons do not undergo spongiform changes (2,11,12). Infection of microglia (2,11,13,14), oligodendroglia (15,16), endothelia (2,11,17,18), and only rarely astocytes (11) has been reported to occur in areas undergoing neuropathology, and because vacuolation is focally associated with infection (19), these findings suggest that neuronal degeneration is an indirect consequence of the infection of other CNS cell types. Nonetheless, it remains unclear which viral targets, alone or in combination, are required for disease induction. ...
The envelope protein (Env) from the CasBrE murine leukemia virus (MLV) can cause acute spongiform neurodegeneration analogous to that induced by prions. Upon CNS infection, Env is expressed as multiple isoforms owing to differential asparagine (N)-linked glycosylation. Because N-glycosylation can affect protein folding, stability, and quality control we explored herein whether unique CasBrE Env glycosylation features could influence neurovirulence. CasBrE Env possesses 6/8 consensus MLV glycosylation sites (gs), but is missing gs3 and gs5, and contains a putative site (gs*). Twenty-nine mutants were generated modifying these three sites, individually or in combination, to mimic the amino acid sequence in the non-neurovirulent MLV Friend 57. Three basic viral phenotypes were observed: replication defective (dead; titer<1 ffu/ml); replication compromised (RC; titer=10(2-5) ffu/ml); and wild-type-like (WTL; titer>10(5) ffu/ml). Env protein was undetectable in dead mutants, while RC and WTL mutants showed variations in Env expression, processing, viral incorporation, viral entry and viral spread. The newly introduced gs3 and gs5 sites were glycosylated whereas gs* was not. Six WTL mutants tested in mice showed no clear attenuation in disease onset or severity, versus controls. Furthermore, three RC viruses tested by neural stem cell (NSC)-mediated brainstem dissemination also induced acute spongiosis. Thus, while unique N-glycosylation affected structural features of Env involved in protein stability, proteolytic processing, virus assembly and entry, these changes had minimal impact on CasBrE Env neurotoxicity. These findings suggest that the Env protein domains responsible for spongiogenesis represent highly stable elements upon which the more variable viral functional domains have evolved.
... To assess whether CNS delivery of env alone could induce spongiform disease, NSCs were engineered into retroviral packaging cells capable of producing infectious but replication-incompetent virus encoding the CasBrE Env protein (SU/TM). Transplantation of these packaging NSCs failed to induce acute spongiosis, despite env dissemination to, and ex-pression within host microglia (33), a major CNS target of MLVs (3,4,20,21,30,52). These latter experiments suggested that MLV-induced spongiform neuropathogenesis might require host cell expression of certain non-Env retroviral proteins or, alternatively, the disease might require CasBrE env virus delivery to, and protein expression within, host cells other than, or in addition to, microglia. ...
... Because several studies have implicated oligodendrocytes as important viral targets in MLV-induced neurodegeneration (3,10,20,38,41,44), we examined NSC-transplanted mice for MLV Gag and CasBrE Env expression in cells expressing the mature oligodendroglial markers carbonic anhydrase II (CAII) and 2Ј,3Ј-cyclic nucleotide 3Ј-phosphohydrolase (CNPase). As summarized in Table 2, no CasBrE Env-positive cells showed CNPase coexpression in mice receiving brain stem transplants of CasE or CasES NSCs with or without 4070A virus infection. ...
... No coexpression was noted regardless of whether the brains developed spongiosis or not ( Table 2). The lack of astrocyte or neuronal infection in the degenerating brain stem was consistent with previous studies from this and other laboratories that have only rarely observed neurovirulent Env expression within these cells (3,4,26,30). ...
Certain murine leukemia viruses (MLVs) can induce progressive noninflammatory spongiform neurodegeneration similar to that
caused by prions. The primary MLV determinants responsible have been mapped to within the env gene; however, it has remained unclear how env mediates disease, whether non-Env viral components are required, and what central nervous system (CNS) cells constitute the
critical CNS targets. To address these questions, we examined the effect of transplanting engraftable C17.2 neural stem cells
engineered to pseudotype, disseminate, and trans-complement neurovirulent (CasBrE, CasE, and CasES) or non-neurovirulent (Friend and SFF-FE) env sequences (SU or SU/TM) within the CNS using either the “non-neurovirulent” amphotropic helper virus, 4070A, or pgag-polgpt (a nonpackaged vector encoding Gag-Pol). These studies revealed that acute MLV-induced spongiosis results from two separable
activities of Env. First, Env causes neuropathology through unique viral targeting within the CNS, which was efficiently mediated
by ecotropic Envs (CasBrE and Friend), but not 4070A amphotropic Env. Second, Env induces spongiosis through a toxin activity
that is MLV-receptor independent and does not require the coexpression of other viral structural proteins. CasBrE and 4070A
Envs possess the toxin activity, whereas Friend Env does not. Although the identity of the critical viral target cell(s) remains
unresolved, our results appear to exclude microglia and oligodendrocyte lineage cells, while implicating viral entry into
susceptible neurons. Thus, MLV-induced disease parallels prionopathies in that a single protein, Env, mediates both the CNS
targeting and the toxicity of the infectious agent that manifests itself as progressive vacuolar neurodegeneration.
... Microglia are the primary cellular target for ts1; the neuronal degeneration caused by ts1 is likely linked to microglial activation and subsequent release of cytokines and cytotoxins which affect neighbouring motor neurons (27). This fits together with former results showing that the neurovirulence of ts1infected mice correlates with the ability of the virus to infect, replicate in, and activate resident microglia (28). Putative microglia-derived factors are the cytokines TNF-α and interleukin-6 (IL-6) which were shown to be present in higher tissue concentrations in the CNS of ts-1 infected than in noninfected mice (29). ...
Various neurological manifestations of retroviral infections have been reported, including peripheral neuropathy, encephalopathy and neuronal degeneration. After penetration into the central nervous system (CNS) the invading retroviruses meet a unique immunological situation that differs significantly from that in the periphery. Due to the blood-brain barrier with its general access restrictions peripheral T-cells, monocytes and B-cells are only "guests" in the brain; instead the immune balance is shifted in favour of the local innate immunity with microglia, astrocytes, cytokines/chemokines and complement forming the dominating defence network. The present article focuses on the most important retroviral infections and highlights the immunological aspects of the neuropathogenesis induced by selected retroviruses. These aspects include: (i) local and infiltrated immune cells as targets of retroviral infection; (ii) stimulation of the cerebral immunity network by retroviruses and subsequent steps of antiviral defence; and (iii) immune activation products as potential contributors to neural damage in the sensitive brain tissue.
... Importantly, CasBrE does not appear to infect the motor neurons that degenerate; and the macroglia (astrocytes and oligodendroglia) appear to be only minimally infected [7][8][9][10]. Instead, the primary MLV targets in the CNS parenchyma are the microglia, whose infection largely colocalizes with neuropathology [7,8,11,12]. The CNS vascular endothelia are also widely infected by Cas-BrE derived viruses, which appears to be an important means for virus entry into the CNS; however, this infection is not associated with alterations in the blood-brain barrier [13,14]. ...
... The primary MLV sequences harbouring neurovirulence determinants have been mapped to within the env gene [18][19][20][21], however, the mechanism by which env mediates disease is not known. In this regard, it has been observed that NV Env proteins do not appear to specify unique cell tropism, as similar CNS cell type infection, including microglial infection, has been observed between closely related NNs and NVs [12,22]. Moreover, NV Env proteins do not appear to be acutely neurotoxic when expressed in the brains of susceptible mice. ...
Background:
Certain murine leukemia viruses (MLVs) are capable of inducing progressive spongiform motor neuron disease in susceptible mice upon infection of the central nervous system (CNS). The major CNS parenchymal target of these neurovirulent retroviruses (NVs) are the microglia, whose infection is largely coincident with neuropathological changes. Despite this close association, the role of microglial infection in disease induction is still unknown. In this paper, we investigate the interaction of the highly virulent MLV, FrCasE, with microglia ex vivo to evaluate whether infection induces specific changes that could account for neurodegeneration. Specifically, we compared microglia infected with FrCasE, a related non-neurovirulent virus (NN) F43/Fr57E, or mock-infected, both at a basic virological level, and at the level of cellular gene expression using quantitative real time RT-PCR (qRT-PCR) and Afffymetrix 430A mouse gene chips.
Results:
Basic virological comparison of NN, NV, and mock-infected microglia in culture did not reveal differences in virus expression that provided insight into neuropathogenesis. Therefore, microglial analysis was extended to ER stress gene induction based on previous experiments demonstrating ER stress induction in NV-infected mouse brains and cultured fibroblasts. Analysis of message levels for the ER stress genes BiP (grp78), CHOP (Gadd153), calreticulin, and grp58 in cultured microglia, and BiP and CHOP in microglia enriched fractions from infected mouse brains, indicated that FrCasE infection did not induce these ER stress genes either in vitro or in vivo. To broadly identify physiological changes resulting from NV infection of microglia in vitro, we undertook a gene array screen of more than 14,000 well-characterized murine genes and expressed sequence tags (ESTs). This analysis revealed only a small set of gene expression changes between infected and uninfected cells (<18). Remarkably, gene array comparison of NN- and NV-infected microglia revealed only 3 apparent gene expression differences. Validation experiments for these genes by Taqman real-time RT-PCR indicated that only single Ig IL-1 receptor related protein (SIGIRR) transcript was consistently altered in culture; however, SIGIRR changes were not observed in enriched microglial fractions from infected brains.
Conclusion:
The results from this study indicate that infection of microglia by the highly neurovirulent virus, FrCasE, does not induce overt physiological changes in this cell type when assessed ex vivo. In particular, NV does not induce microglial ER stress and thus, FrCasE-associated CNS ER stress likely results from NV interactions with another cell type or from neurodegeneration directly. The lack of NV-induced microglial gene expression changes suggests that FrCasE either affects properties unique to microglia in situ, alters the expression of microglial genes not represented in this survey, or affects microglial cellular processes at a post-transcriptional level. Alternatively, NV-infected microglia may simply serve as an unaffected conduit for persistent dissemination of virus to other neural cells where they produce acute neuropathogenic effects.
... We have proposed that glial cells carrying viral antigens might contribute to developing neuropathological lesions induced by A8-V infection, because we often observe the antigen positive glial cells attaching to the walls of vacuoles which compose spongiotic lesions (17,21). In addition, numerous reports have suggested that spongiform degeneration induced by neuropathogenic murine retroviruses is primarily associated with infection of microglial cells (1,3,6,12). The results of our double labeling study confirmed that A8-V infection also induces many microglial cells which carry viral antigens (Fig. 2F). ...
A8-V and PVC211 are neuropathogenic strains of the Friend murine leukemia virus (Fr-MLV) that cause spongiosis in the rat brain after infection at birth. PVC211 exhibited stronger neuropathogenicity than A8-V, and induced more severe neurological symptoms such as hind-leg paralysis. These symptoms correlated with the neuropathological spread and intensity, which were more severe in the spinal cord of rats infected with PVC211 than in those infected with A8-V, without exhibiting neuropathological differences in other areas of the CNS. Interestingly, virus titers recovered from infected spinal cords were similar in PVC211 and A8-V infected animals. However, in the spinal cord infected with PVC211, glial cells attained higher immunohistochemical expression scores for the viral surface antigen, gp70 (Env) than in the A8-V infected spinal cord, although expression levels of viral antigens in blood vessel walls were similar in A8-V and PVC211 infections. Furthermore, many of those glial cells which carried viral antigens were found, by double immunostaining, to be microglia. The results suggested that the spread of viral antigen positive microglia plays an important role in forming the different neuro-pathogenicity observed in A8-V and PVC211 infections.
... These env Tg mice developed typical spongiform lesions. ts-1 and Cas-Br-E MuLVs replicate preferentially in microglial cells and to a certain extent in endothelial cells (8,9,18,36,58,72,73,93), while a third neurovirulent MuLV, PVC-211, replicates mainly in the brain capillary endothelial cells (42,75). Although replication has been reported by one study to occur in motor neurons (95), this observation has not been confirmed by other studies (36,58,72). ...
Some murine leukemia viruses (MuLVs), among them Cas-Br-E and ts-1 MuLVs, are neurovirulent, inducing spongiform myeloencephalopathy and hind limb paralysis in susceptible mice. It has been shown that the env gene of these viruses harbors the determinant of neurovirulence. It appears that neuronal loss occurs by an indirect mechanism, since the target motor neurons have not been found to be infected. However, the pathogenesis of the disease remains unclear. Several lymphokines, cytokines, and other cellular effectors have been found to be aberrantly expressed in the brains of infected mice, but whether these are required for the development of the neurodegenerative lesions is not known. In an effort to identify the specific effectors which are indeed required for the initiation and/or development of spongiform myeloencephalopathy, we inoculated gene-deficient (knockout [KO]) mice with ts-1 MuLV. We show here that interleukin-6 (IL-6), inducible nitric oxide synthetase (iNOS), ICE, Fas, Fas ligand (FasL), and TNF-R1 KO mice still develop signs of disease. However, transgenic mice overexpressing Bcl-2 in neurons (NSE/Bcl-2) were largely protected from hind limb paralysis and had less-severe spongiform lesions. These results indicate that motor neuron death occurs in this disease at least in part by a Bcl-2-inhibitable pathway not requiring the ICE, iNOS, Fas/FasL, TNF-R1, and IL-6 gene products.
... Once virus is disseminated within the parenchyma, microglia infection occurs, followed by region-specific degeneration of neuronal elements (Czub et al., 1994; Lynch et al., 1995 Lynch et al., , 1996 Robertson et al., 1997). It is important to emphasize that the neurons which degenerate in this disease are not infected by murine leukemia viruses (MuLVs), and any proliferating neurons which do become infected are not adversely affected (Baszler and Zachary, 1991; Kay et al., 1991; Lynch et al., 1991). Thus, microglial infection indirectly mediates neuropathological changes, although how microglial function is altered by neurovirulent virus infection is not yet known. ...
The 4070A amphotropic murine leukemia virus (A-MuLV) has been variably reported to harbor neurovirulence determinants within its env gene. In this report we reexamined this issue by applying two approaches previously demonstrated to amplify murine leukemia virus neurovirulence. The first approach involved introducing the 4070A env gene into the background of Friend virus clone FB29 to enhance peripheral virus replication kinetics and central nervous system entry. The resulting chimeric virus, FrAmE, exhibited widespread vascular infection throughout the central nervous system (CNS); however, parenchymal infection was quite limited. Neither clinical neurological signs nor spongiform neurological changes accompanied FrAmE CNS infection. To overcome this CNS entry limitation, 4070A and FrAmE were delivered directly into the CNS via transplantation of infected C17.2 neural stem cells (NSCs). Significantly, NSC dissemination of either 4070A or FrAmE resulted in widespread, high-level amphotropic virus expression within the CNS parenchyma, including the infection of microglia, the critical target required for inducing neurodegeneration. Despite the extensive CNS infection, no associated clinical neurological signs or acute neuropathological changes were observed. Interestingly, we observed the frequent appearance of circulating polytropic (MCF) virus in the serum of amphotropic virus-infected animals. However, neither peripheral inoculation of an amphotropic/MCF virus mixture nor transplantation of NSCs expressing both amphotropic and MCF viruses induced acute clinical neurological signs or spongiform neuropathology. Thus, the results generated in this study suggest that the 4070A env gene is not inherently neurovirulent. However, the frequent appearance of endogenous MCF viruses suggests the possibility that the interactions of amphotropic viruses with endogenous retroviral elements could contribute to the development of retrovirus-induced neurodegenerative disease.
