Location and distribution of virus antigen in the central nervous system of mice persistently infected with Theiler's virus

The present study has shown that virus can be readily detected by immunofluorescent staining in the central nervous system (CNS) of SJL mice persistently infected with Theiler's murine encephalomyelitis virus (TMEV). Considering the low CNS virus content, large amounts of virus antigen were found in the white matter, the site of demyelinating lesions. Virus antigen was detected in all animals killed after post-infection (PI) Day 21, a time which can be considered as the beginning of the persistent phase of this infection, and the appearance of virus antigen in white matter corresponded closely in time with the onset of demyelination. The pathogensis of this persistent infection can now be reasonably well reconstructed from the temporal observations made in this study. It would appear that between the second and third week PI, virus replication largely shifts from neurons in spinal cord gray matter to other cell types located in white matter. While a lower-grade persistent infection (in terms of the relative number of cells containing virus antigen) is established and maintained in cells in the gray matter and inflammatory and leptomeningeal infiltrates, cells in white matter appear to be mainly responsible for perpetuating the infection. Why these cells should supplant neurons as the most susceptible host cell during the chronic phase of the infection is discussed.     

Theiler''s virus infection in mice: an unusual biphasic disease process leading to demyelination.

An unusual biphasic central nervous system disease developed in 3-week-old Swiss outbred mice after intracerebral inoculation of the DA strain of Theiler's murine encephalomyelitis virus. Nine to 20 days postinfection 86% of mice became paralyzed, and approximately one-half of these animals survived. During this period neuronal necrosis and microglial proliferation were seen in thalamus, brainstem, and spinal cord. There was an initial phase of virus growth in spinal cord followed by persistent infection at a lower concentration. Virus antigen was readily found in the cytoplasm of neurons by immunofluorescent staining early in the course of infection, whereas after 30 days there was a paucity of cells containing virus antigen which were present only in the spinal cord white matter. Between 1 and 5 months, an intense mononuclear inflammatory cell lesion evolved in the spinal cord leptomeninges and white matter, which coincided with a mild gait disturbance in some surviving mice, and patchy demyelination was found in areas of inflammation. The acute gray matter pathology would appear to be the result of direct virus lytic effect. Although the late white matter lesion culminating in demyelination probably represents a cytocidal infection similar to the situation that exists in certain picornavirus carrier culture systems, a virus-induced immunopathological process merits further study.     

Contrasting effects of immunosuppression on Theiler''s virus infection in mice.

In the present study, cyclophosphamide and rabbit anti-mouse thymocyte serum were used to immunosuppress SJL/J mice infected with Theiler's mouse encephalomyelitis virus (TMEV) in order to delineate the potential mechanism(s) of virus-induced cellular injury in this infection. Whereas both immunosuppressive agents produced a significant increase in mortality, this treatment had differing effects on the pathological involvement of gray and white-matter structures in the central nervous system. The central nervous system of immunosuppressed TMEV-infected mice had increased microglial cell proliferation and neuronal necrosis, longer maintenance of high virus levels and spread of virus antigen to involve the neocortex and hippocampal complex. These observations indicate that TMEV causes a cytolotic infection of neurons and possibly other cells in gray matter. In contrast, immunosuppression produced a dramatic reduction in mononuclear inflammatory cells in the leptomeninges and spinal cord white matter of infected mice and prevented demyelination. Further, virus antigen was not detected in the leptomeninges and white matter of immunosuppressed and infected mice. These findings suggest that demyelination of TMEV infection is immune mediated.     

Ultrastructural immunohistochemical localization of virus in acute and chronic demyelinating Theiler's virus infection.

Mice experimentally infected with Theiler's murine encephalomyelitis virus (TMEV) develop a persistent infection of the central nervous system (CNS). The most striking feature of this infection is the occurrence of inflammatory primary demyelination in the spinal cord white matter. The pathogenesis of myelin degeneration in this model has not been clarified, but morphologic and immunologic data suggest that the host immune response plays a major role in the production of myelin injury. Because of low virus titers in infected adult mice and of the small size of TMEV, virus particles have never been observed in this demyelinating model. Yet elucidation of the types of cells in the CNS supporting virus replication would be important for a better understanding of both virus persistence and virus-induced demyelinating pathology. The present paper is a sequential study of the localization of TMEV in the spinal cord in infected mice by ultrastructural immunohistochemical techniques. Results indicate that virus replication is mainly in neurons during the acute phase of the disease, while in the chronic phase viral inclusions are mainly found in macrophages in and around demyelinating lesions. Other cells are also infected, but to a lesser degree. In the neuronal system both axoplasmic and dendritic flow appear to facilitate the spread of virus in the CNS. In macrophages, the presence of virus particles and the association of virus with altered components of the cytoskeleton support active virus production rather than simple internalization. The macrophage appears to play an important role in both the establishment of virus persistence and in the process of demyelination in this animal model.     

Correlation between presence of lactate dehydrogenase-elevating virus RNA and antigens in motor neurons and paralysis in infected C58 mice

Lactate dehydrogenase-elevating virus (LDV) induces poliomyelitis in immunosuppressed C58 mice resulting in fatal paralysis. We have synthesized and cloned cDNA complementary to the LDV genome, and used the cDNA clones as in situ hybridization probes for the detection of LDV RNA in tissue sections. Direct fluorescent antibody staining using IgG from chronically infected mice was used for the detection of LDV antigens. Using these methods, we have detected LDV RNA and antigens in anterior horn neurons of paralyzed mice. The appearance of LDV RNA and antigen positive motor neurons and their location in the spinal cord correlated with the development of paralytic symptoms. No positive neurons were detected in LDV-infected, susceptible mice without signs of paralysis, but some glial cells of the white and gray matter in the spinal cords of these mice were found to contain LDV RNA. These analyses broaden the host cell range of LDV to include neuronal and other cells in the CNS and support the hypothesis of LDV replication in neurons as the cause of poliomyelitis and paralysis.     

Immunohistochemical localization of neurotropic ecotropic murine leukemia virus in moribund mice

The CasBrE strain of neurotropic ecotropic murine leukemia virus (NE-MuLV) infects susceptible mice and induces a noninflammatory, slowly degenerative nervous system disease. We employed immunohistochemistry to identify which cells in the nervous system and other tissues contained viral antigen in the chronically infected mouse. Rabbit antiserum to the virus was prepared using different combinations of whole virus and synthetic peptides corresponding to a 14-amino-acid sequence of the viral envelope protein. Twenty-four of forty-four (55%) mice neonates inoculated intracranially with NE-MuLV developed symptoms ranging from tremulousness to hindlimb paralysis within 3-9 months. They were subsequently sacrificed and their tissues used for histology and immunohistochemistry. The major locations of viral antigen outside of the central nervous system (CNS) were skeletal muscle and spleen. Skeletal muscle was the only non-nervous system tissue that exhibited degenerative changes as atrophy of viral antigen-bearing oxidative myofibers. In the CNS, viral antigen was detected in neurons, endothelium, and glial cells. Immunohistochemical double-labeling studies for viral antigen and the astrocytic marker glial acidic fibrillary protein (GFAP) demonstrated that the viral antigen-containing glia were oligodendrocytes and not astrocytes. Tissue damage in the brain consisted of vacuolar changes and gliosis principally in the brainstem. Viral antigen was most abundantly localized in these regions of pathologic change. In the spinal cord a different pattern was observed. Although tissue damage was observed throughout the cord, viral antigen was located at the border of the gray and white matter. These findings indicate direct and indirect virus-mediated mechanisms of damage to the CNS.     

Remyelination during remission in Theiler's virus infection.

Inoculation of the cell-adapted WW strain of Theiler's virus into mice produces a chronic demyelinating infection of the central nervous system (CNS) characterized by a remitting relapsing course. During remission, extensive remyelination of spinal cord white matter is observed. Remyelination is carried out by both Schwann cells and oligodendrocytes. This paper examines the possible mechanisms of entry of Schwann cells into the CNS, their possible source in different regions of the white matter, their relations with various CNS elements, and the relative activity of these cells versus that of oligodendrocytes. Observations suggest that Schwann cells, originating from peripheral roots and from perivascular areas, migrate into white matter through gaps in the glial limiting membrane ( GLM ), probably caused by active mononuclear inflammatory cells. Schwann cell invasion and axonal contact appear to be facilitated by the presence of collagen matrix along their pathway of migration. No alterations of astrocytes in the immediate vicinity of Schwann cells were observed, and free contact between Schwann cells and different neuroglial elements was present in the initial stages of Schwann cell migration. While Schwann cells were the predominant myelinating cells in the outer white matter, oligodendrocytes were numerous and very active in the inner portions of the spinal cord column. Although oligodendrocytes produced thinner myelin than normal, in most areas essentially complete remyelination by these cells was observed. These results contrast with those of previous studies of DA infected mice in which remyelination is sporadic in the presence of unabated inflammation which continues without remission for many months after infection. It is suggested that oligodendroglial cells are quite capable of extensive remyelinating activity in this infection, provided the noxa responsible for myelin injury subsides. The host inflammatory response appears to be the most likely noxa impeding remyelination in this model.     

Preferential adhesion of chick central neurons to the gray matter of the central nervous system

Dissociated chick neocortical neurons were cultured on cryostat sections of the rat central nervous system. The neurons adhered to and grew on the gray matter of the tissue derived from various parts of the central nervous system (CNS), but were not seen on the white matter. However, cell attachment was seen on sciatic nerve. This preferred adhesion to and growth on the gray matter of the CNS was abolished by irradiation of ultraviolet light which is supposed to denaturate proteins without disturbing tissue architecture. These observations suggest that differential cell adhesion to the gray and white matter could be ascribable to localization of some adhesive molecule(s) in the gray matter or to localization of nonpermissive molecule(s) in the CNS gray matter.     

Early events in the pathogenesis of eastern equine encephalitis virus in mice

To elucidate the pathogenesis of eastern equine encephalitis (EEE) virus infections, we used histopathology, immunohistochemistry, and in situ hybridization to track the spread and early cellular targets of viral infection in mice. Young mice were inoculated with virulent EEE virus in their right rear footpad and were followed in a time-course study for 4 days. Virulent EEE virus produced a biphasic illness characterized by an early self-limiting replication phase in peripheral tissues followed by an invariably fatal central nervous system (CNS) phase. In the early extraneural phase, there was primary amplifying replication of virus within fibroblasts at the inoculation site and within osteoblasts in active growth areas of bone that resulted in a transient high-titer viremia. Pathological changes and viral infection were observed as early as 12 hours post-infection (PI) in osteoblasts, skeletal muscle myocytes, and in fibroblasts along fascial sheaths. The severity and extent of infection in peripheral tissues peaked at day 1 PI. In the neural phase of infection, virus was first detected in the brain on day 1 PI, with rapid interneuronal spread of infection leading to death by day 4 PI. EEE virus appeared to be directly cytopathic for neurons. The very rapid onset and apparently random and widely dispersed infection in the CNS, with concurrent sparing of olfactory neuroepithelium, strongly suggests that invasion of the CNS by EEE occurs by a vascular route, rather than via peripheral nerves or the olfactory neuroepithelium. Our finding that metaphyseal osteoblasts are an early site of amplifying viral replication may explain the higher-titer viremias and higher incidence of neuroinvasion and fulminant encephalitis seen in the young, and may also explain why mature animals become refractory to encephalitis after peripheral inoculation with EEE virus.     

In vivo and in vitro models of demyelinating disease. XVII. The infectious process in athymic rats inoculated with JHM virus

Wistar Lewis (WL), Long Evans (LE) and other rat strains develop complete resistance to CNS disease when inoculated intracerebrally with murine hepatitis JHM virus (JHMV) after the 10th day of age. Two types of studies were conducted to ascertain the involvement of the cellular immune system in development of resistance. Immunosuppression of WL rats with cyclosporin A (CsA) following onset of the age-related resistance demonstrated that this drug was partially able to abrogate resistance. In the other studies nude (rnu/rnu) rats, their heterozygous (rnu/+) litter mates and genetically related LE rats of various ages were challenged with JHMV. The rnu/+ and LE animals became completely resistant before the age of weaning, whereas some rnu/rnu rats, challenged as late as 70 days of age, showed disease symptoms--albeit after a long latent period. These observations indicated that the cellular immune system plays an important role in suppressing the disease process in the CNS. When the infection of nude rats was initiated on or after the 15th day of life, the histological lesions were generally small and present in both grey and white matter but were seldom seen in the spinal cord. Mononuclear infiltrates were evident throughout the CNS. In some nude rats there was massive mononuclear cell infiltration towards the meningies and into ventricular spaces. By contrast in mu/+, LE and WL rats with late-onset disease symptoms, demyelinating-type lesions were confined to the white matter and only minor infiltration of mononuclear cells was evident. JHMV RNA was detectable by dot-blotting analysis in the CNS of both paralysed and asymptomatic rnu/rnu and rnu/+ rats, but less RNA was usually detected in heterozygous animals. In-situ hybridization with cDNA probes for JHMV RNA showed that neurons in the hippocampus and cerebellum, as well as cells in the white matter, were frequently infected. The present data indicate that in the rat T cells have an important function in maintaining resistance to the JHMV related disease process. However, even without a functional T cell compartment nude rats challenged after 15 days of age did not develop an acute encephalitis, suggesting that an age-dependent, non-immunological mechanism is also involved in restricting the spread of infection. It is possible that resistance in euthymic rats sets in because: (1) at the time of weaning the CNS matures, so that the number of targets available for infection is reduced, (2) T cells prevent the late-onset disease by clearing persistent, low grade infections from the CNS.     

Fatal fulminant pan-meningo-polioencephalitis due to West Nile virus

We report a case of fatal fulminant West Nile virus (WNV) meningoencephalitis in an 87-year-old white male gardener. The Pennsylvania patient presented with a 3-day history of flu-like symptoms. His hospital course was gravely precipitous with onset of coma, ventilator dependence, loss of cortical and brainstem functions within ten days of admission. Acute serum and cerebrospinal fluid samples revealed elevated levels of WNV IgM antibodies by ELISA as well as elevated CSF white blood cells, protein and glucose. A complete autopsy revealed a multifocal lymphocytic myocarditis and severe chronic tubulointerstitial nephritis. Viral culture and PCR analysis of post-mortem samples of the spleen, kidney and brain were positive for WNV. Histological sections from all regions of the brain and spinal cord demonstrated a severe, non-necrotizing, subacute, polio-meningoencephalitis. While both gray and white matter were inflamed, gray matter was much more severely involved. Many gray matter nuclei showed severe neuronal loss with residual dying neurons surrounded by activated microglia. Immunohistochemical stains revealed profuse infiltration of the meninges and cerebral parenchyma by CD8 T-lymphocytes and perivascular B-lymphocytes. Electron micrographs revealed diffuse intracellular and extracellular edema but no viral particles were identified. Immunohistochemical and immunofluorescent staining for WNV filled the cytoplasm of residual neurons. West Nile virus mediates a predominantly polioencephalitis secondary to direct infection of neurons.     

Host age and cell type influence measles virus protein expression in the central nervous system

Measles virus infection of the central nervous system (CNS) of children can result in a slow, progressive fatal disease, subacute sclerosing panencephalitis (SSPE). The pathogenesis of persistent measles virus infection of the CNS has been studied by comparing viral protein expression in suckling or weanling hamsters infected with the HBS strain of measles virus. Suckling animals develop a rapidly progressive fatal encephalitis while weanling animals survive and are persistently infected. Viral nucleocapsid (NP) and hemagglutinin (H) proteins have been examined during acute infection in suckling and weanling animals. Viral H protein expression is selectively inhibited in infected neurons of weanling animals, while infected ependymal cells retain the capability to express H protein at the cell surface; suckling animals express high levels of both proteins. Anti-measles antibodies are not responsible for the inhibition of H protein since immunosuppression does not restore protein expression. The cell-associated virus which is recovered late in infection by co-cultivation with Vero cells expresses all viral proteins. These results suggest that intact viral genome is present in persistent infections, and cell type or state of differentiation of infected cells may be instrumental in expression of viral proteins which can influence lytic or persistent outcome of infection.     

Human herpesvirus-6 (HHV-6)-associated necrotizing encephalitis in griscelli's syndrome

We report a male caucasian German pediatric patient of no Arab or Mediterranean ancestry with virus associated CNS lesions in Griscelli's syndrome (GS; McKusick No. 214450). The boy presented with recurrent infections, and meningitis with subsequent progressive signs of increased intracranial pressure leading to death at 32 weeks of age. At autopsy, various sites of the CNS revealed necroses in gray and white matter. CNS histology revealed numerous and massive predominantly perivascular CD8 positive lymphohistiocytic infiltrates. These findings were associated strictly with the presence of human herpesvirus-6 (HHV-6) genome or the HHV-6 specific late antigen H-AR 3, found in neurons, oligodendrocytes, and astrocytes. The search for HHV-6 replication dependent antigen, HHV-7 DNA, CMV, adenovirus, Coxsackie B1, B2, and B4-antigens, and mycobacteria was not successful. Detection of viruses was attempted using immunohistochemistry, in situ hybridization or nested polymerase chain reaction, respectively. Lymphocyte typing was carried out immunohistochemically. In GS, virus induced CNS damage does not seem to require necessarily active virus replication. It may also appear as a consequence of an immune reaction triggered by antigen expression. J. Med. Virol. 53:306–312, 1997. © 1997 Wiley-Liss, Inc.     

Severer nodular lesion in white matter than in gray matter in simian immunodeficiency virus-infected monkey,but not closely correlated with viral infection

Immune cell accumulation and white matter anomaly are common features of HIV (human immunodeficiency virus) -infected patients in combination antiretroviral therapy (cART) era. Neuroimaging tests on cART treated patients displayed prominent diffuse white matter lesions. Notably, immune cell nodular lesion (NL) was a conspicuous type of pathological change in HIV/SIV (simian immunodeficiency virus) infected brain before cART. Therefore, we used SIV infected brain to investigate the distribution of those NLs in gray and white matters. We found a significant higher number of NLs in white matter than that in gray matter. However, virus infection correlated with macrophage NLs but not with microglia NLs, especially in white matter. In addition, NLs interrupted white matter integrity more severely, since even tiny nodules could disconnect nerve fibers in white matter tracts. In the gray matter with dense myelinated axons, NLs obviously encroached those fibers; in the area of few myelinated axons, small nodules well co-localized with extracellular matrix between neurons.     

Quantitative study of the infection in brain neurons in human rabies

Rabies virus is a highly neuronotropic virus that causes encephalomyelitis. Rabies virus infection was studied in neurons in the brain of an 8-year-old girl that died of rabies in Mexico. The extent of the neuronal infection was evaluated quantitatively in neuronal cell types of the brain using histologic staining for Negri bodies and immunoperoxidase staining for rabies virus antigen in the same neurons. Quantitative image analysis was used to compare the amount of infection in five different neuronal cell types, which was expressed as a percentage of neuronal area. Purkinje cells and periaqueductal gray neurons showed the largest percentage area for both Negri bodies and signal for rabies virus antigen. In general, there was a good linear relationship between the area of Negri bodies and the area of signal for rabies virus antigen. Many neurons with rabies virus antigen did not have Negri bodies, however, and some neurons with large antigen signals, especially Purkinje cells and periaqueductal gray neurons, lacked Negri bodies. Formation of Negri bodies is likely influenced by factors that vary in different neuronal cell types.     

外周血淋巴细胞携带风疹抗原与中枢神经感染风疹病毒的关系

目的　探讨外周血淋巴细胞携带风疹病毒抗原与风疹病毒感染中枢神经系统的关系。方法　BALB/c小鼠分别给予临床常用的可影响机体免疫功能的药物 ,再经腹腔感染风疹病毒 ,并在感染后的 1、3、7、14d观察外周血淋巴细胞携带病毒抗原的情况 ,分析其与中枢神经系统病毒感染的关系。结果　地塞米松药物组在不同时间抗原的平均携带率分别为 3 1%、4 1%、9 6 %、2 4% ,环磷酰胺药物组分别为 14 2 %、12 7%、9 9%、3 1% ,未用药物干预的感染组分别为 4 6 3 %、10 2 5 %、6 88%、1 75 %。方差分析显示 ,3组动物在感染风疹病毒后的第 2 4小时外周血淋巴细胞携带抗原存在明显差异 ,F =0 0 317,P <0 0 5。组间两两比较结果显示 :环磷酰胺药物组动物外周血淋巴细胞抗原的携带明显高于其它实验动物组 ,地塞米松药物组和药物未干预组动物之间无明显差异。确切概率法分析表明 ,动物外周血淋巴细胞风疹病毒的持续性携带与中枢神经系统风疹病毒感染的关系极为密切 ,P <0 0 0 1。结论　环磷酰胺可能影响风疹病毒感染后外周血淋巴细胞对病毒的携带率。在感染初期 ,外周血淋巴细胞持续携带风疹病毒将增大中枢神经系统感染的机会     

The major site of murine K papovavirus persistence and reactivation is the renal tubular epithelium.

K virus, a murine papovavirus, produces a lethal pneumonia in newborn mice. Animals surviving acute illness develop a persistent infection which reactivates under conditions of immunosuppression. The present study was conducted to identify the cell populations which support persistent K virus infection and to determine the cell populations in which this persistent infection is reactivated during immunosuppression. Mice inoculated by the oral route with 100 50% newborn mouse lethal doses (LD50) of K virus at 14 days of age were followed over a period of 7 months. The distribution of infection was studied by virus assay, immunohistochemistry, and in situ nucleic acid hybridization methods. Viral replication during the acute phase of infection was confined to pulmonary and systemic vascular endothelial cells, as well as to scattered, apparently lymphoid cells within spleens. Beginning 2 months after inoculation, however, specific hybridization for K virus nucleic acids was detected in rare renal tubular epithelial cells, and by 6 months after inoculation renal tubular epithelial cells represented the major site of viral persistence. Positive cells were frequently present in groups of two or more, and a minority of positive cells also expressed viral capsid (V) antigen. Immunosuppression with cyclophosphamide resulted in reactivation of infection, with highest titers of virus being detected in kidneys and with increased numbers of renal tubular epithelial cells expressing viral capsid antigen. Capsid antigen was also detected in rare endothelial cells in kidneys, livers and lungs of these immunosuppressed mice. Although K virus behaves as an endotheliotrope during acute infection, the major site of K virus persistence and reactivation, the renal tubular epithelial cell, is similar to that involved during persistent infection by polyoma virus in mice, SV40 virus in monkeys, and BK and JC viruses in man. The observation that persistently infected renal tubular epithelial cells occur in groups of two or more and occasionally express capsid antigen suggests that virus may persist as a productive infection which is confined by antiviral antibody but maintains itself by cell-to-cell-spread. The present study represents the first instance in which the cell populations which support infection by a member of the polyomavirus subgroup in its natural host have been defined during acute, persistent, and reactivated infection.     

Axonal injury heralds virus-induced demyelination

Axonal pathology has been highlighted as a cause of neurological disability in multiple sclerosis. The Daniels (DA) strain of Theiler's murine encephalomyelitis virus infects the gray matter of the central nervous system of mice during the acute phase and persistently infects the white matter of the spinal cord during the chronic phase, leading to demyelination. This experimental infection has been used as an animal model for multiple sclerosis. The GDVII strain causes an acute fatal polioencephalomyelitis without demyelination. Injured axons were detected in normal appearing white matter at 1 week after infection with DA virus by immunohistochemistry using antibodies specific for neurofilament protein. The number of damaged axons increased throughout time. By 2 and 3 weeks after infection, injured axons were accompanied by parenchymal infiltration of Ricinus communis agglutinin I(+) microglia/macrophages, but never associated with perivascular T-cell infiltration or obvious demyelination until the chronic phase. GDVII virus infection resulted in severe axonal injury in normal appearing white matter at 1 week after infection, without the presence of macrophages, T cells, or viral antigen-positive cells. The distribution of axonal injury observed during the early phase corresponded to regions where subsequent demyelination occurs during the chronic phase. The results suggest that axonal injury might herald or trigger demyelination.     

Localization of simian immunodeficiency virus in the central nervous system of rhesus monkeys.

Simian immunodeficiency virus (SIV), like the human immunodeficiency virus (HIV), is a lentivirus that is both immunosuppressive and neurovirulent. Rhesus macaques (Macaca mulatta) inoculated with SIV often develop a giant cell encephalitis similar to that seen in humans infected with HIV. The authors examined SIV expression by immunohistochemistry and RNA in situ hybridization in the cerebrum, cerebellum, choroid plexus, and spinal cord from five macaques with and two macaques without giant cell encephalitis. Selected portions of the central nervous system (CNS) also were examined by electron microscopy. Simian immunodeficiency virus was detected in the CNS of all seven monkeys whether or not they had giant cell encephalitis. Both SIV antigen and RNA were present in all levels of the CNS examined. Macrophage/giant cell lesions always contained viral RNA and antigen and were the only sites where viral particles were detected by electron microscopy. However, SIV antigen and RNA also were commonly associated with small vessels, the choroid plexus, and meninges; these were the only locations where virus was detected in animals without giant cell encephalitis. Immunophenotyping showed that the cellular infiltrates consisted primarily of monocyte/macrophages and occasional CD8-positive T cells. Macrophages and T cells also were present in the stroma of the choroid plexus and were intimately associated with vessels in the CNS of SIV-infected but not uninfected macaques. Simian immunodeficiency virus infection of the macaque CNS provides an excellent model for studying the pathogenesis, treatment, and prevention of HIV-1-encephalitis.     

Monocytes/macrophages isolated from the mouse central nervous system contain infectious Theiler's murine encephalomyelitis virus (TMEV)

Knowledge of the cells in which Theiler's murine encephalomyelitis virus (TMEV) persists is crucial to understanding the pathogenesis of TMEV-induced demyelinating disease; however, it is still uncertain whether oligodendrocytes or macrophages are the primary target for persistence. In this study, mononuclear cells (MNC) isolated directly from central nervous system (CNS) inflammatory infiltrates of TMEV-infected mice on discontinuous Percoll gradients were found to contain infectious TMEV. Macrophages appeared to be the principal MNC infected as determined by two-color immunofluorescence. Infectious center assay and double immunostaining together indicated the presence and possible synthesis of TMEV in approximately 1 in 225 to 1 in 1000 CNS macrophages, with 1 to 7 PFU produced per macrophage. On the basis of these findings, limited replication in macrophages is consistent with the total CNS virus content detected at any time during the persistent phase of the infection as well as the slow pace of the infection.