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Neurologic Disease Induced by Polytropic Murine Retroviruses: Neurovirulence Determined by Efficiency of Spread to Microglial Cells

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Neurologic Disease Induced by Polytropic Murine Retroviruses: Neurovirulence Determined by Efficiency of Spread to Microglial Cells JOURNAL OF VIROLOGY, July 1997, p. 5287–5294 Vol. 71, No. 7 0022-538X/97/$04.0010 Copyright © 1997, American Society for Microbiology Neurologic Disease Induced by Polytropic Murine Retroviruses: Neurovirulence Determined by Efficiency of Spread to Microglial Cells SHELLY J. ROBERTSON, KIM J. HASENKRUG, BRUCE CHESEBRO, AND JOHN L. PORTIS* Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840 Received 10 May 1996/Accepted 26 March 1997 Several murine leukemia viruses (MuLV) induce neurologic disease in susceptible mice. To identify features of central nervous system (CNS) infection that correlate with neurovirulence, we compared two neurovirulent MuLV, Fr98 and Fr98/SE, with a nonneurovirulent MuLV, Fr54. All three viruses utilize the polytropic receptor and are coisogenic, each containing a different envelope gene within a common genetic background. Both Fr98 and Fr98/SE induce a clinical neurologic disease characterized by hyperexcitability and ataxia yet differ in incubation period, 16 to 30 and 30 to 60 days, respectively. Fr54 infects the CNS but fails to induce clinical signs of neurologic disease. In this study, we compared the histopathology, regional virus distribution, and cell tropism in the brain, as well as the relative CNS viral burdens. All three viruses induced similar histopathologic effects, characterized by intense reactive astrogliosis and microglial activation associated with minimal vacuolar degeneration. The infected target cells for each virus consisted primarily of endothelial and microglial cells, with rare oligodendrocytes. Infection localized predominantly in white matter tracts of the cerebellum, internal capsule, and corpus callosum. The only feature that correlated with relative neuroviru- lence was viral burden as measured by both viral CA protein expression in cerebellar homogenates and quantification of infected cells. Interestingly, Fr54 (nonneurovirulent) and Fr98/SE (slow disease) had similar viral burdens at 3 weeks postinoculation, suggesting that they entered the brain with comparable efficiencies. However, spread of Fr98/SE within the brain thereafter exceeded that of Fr54, reaching levels of viral burden comparable to that seen for Fr98 (rapid disease) at 3 weeks. These results suggest that the determinants of neurovirulence in the envelope gene may influence the efficiency of virus spread within the brain and that a critical number of infected cells may be required for induction of clinical neurologic disease. Retroviruses are important human and animal pathogens is different from the paralytic diseases induced by the ecotropic associated with a number of neoplastic, immunodeficiency, and MuLV (39). chronic degenerative disorders. They are also the etiologic Similar to the ecotropic viruses (12), the determinants for agents of certain diseases affecting the nervous system. Retro- neurovirulence in FMCF98 reside within the envelope gene. viruses, including primate and animal lentiviruses (8, 22, 31, 32, This was demonstrated by the construction of a chimeric virus, 34, 36, 37, 40), human T-cell leukemia virus type 1 (29), and Fr98 (formerly named Fr98E) (39), which contains the 39 pol several murine leukemia viruses (MuLV) (reviewed in refer- and env genes of FMCF98 in the background of FB29, a non- ence 51), induce a spectrum of neurologic deficits affecting neurovirulent strain of Friend MuLV (38). Fr98 induces a behavior, cognitive, and motor functions in their respective clinical disease similar to that induced by FMCF98, but with a hosts. shortened incubation period (39). In contrast, the chimeric Several different types of neurologic disease are induced by polytropic virus clone Fr54, which contains the env gene of a MuLV. Ecotropic Friend strain TR1.3 cause acute fatal cere- nonneurovirulent polytropic isolate, FMCF54, infects the cen- brovascular hemorrhage (35). Other ecotropic viruses, such as tral nervous system (CNS) but causes no neurologic deficits the wild mouse MuLV (CasBrE) (14), the Moloney MuLV (19). (tsMoBA-1) (5, 52), and the Friend MuLV (PVC-211) (20, 23) In the course of mapping studies to identify envelope se- cause more chronic disease manifested by tremor and hindlimb quences that influence neuropathogenicity, we constructed a paralysis. These viruses induce a noninflammatory spongiform series of polytropic viruses containing chimeric envelope genes neurodegeneration involving grey and sometimes white matter composed of segments from the neurovirulent polytropic virus of the neocortex, hindbrain, and spinal cord. Recently, a FMCF98 and the nonneurovirulent virus FMCF54. Like Fr98, Friend mink cell focus-forming virus, FMCF98, has also been all of these viruses had the same FB29 genetic background. shown to be neurovirulent in susceptible mice (6, 39). FMCF98 These studies demonstrated that the viral envelope gene influ- is unique among neurovirulent MuLV because it has a poly- ences relative viral burden in the brain and that, with one tropic receptor specificity (7, 42) and induces a clinical syn- exception, viral burden correlated with relative neurovirulence drome characterized by hyperexcitability and imbalance which (19). Interestingly, the exception was the nonneurovirulent virus Fr54, which exhibited a viral burden, at 2 and 3 weeks after inoculation, comparable to that of one of the neuroviru- * Corresponding author. Mailing address: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of lent viruses, Fr98/SE, which contained a chimeric envelope Allergy and Infectious Diseases, National Institutes of Health, 903 S. gene. These results raised the intriguing possibility that enve- 4th St., Hamilton, MT 59840. Phone: (406) 363-9339. Fax: (406) 363- lope sequences that influence neuroinvasiveness (i.e., the abil- 9204. E-mail: [email protected]. ity to infect the brain) may be separable from those determin- 5287 5288 ROBERTSON ET AL. J. VIROL. ing neurovirulence (i.e., the ability to induce clinical neurologic antibody was a biotinylated goat anti-rat immunoglobulin (Vector Laboratories, disease). This is a particularly relevant issue in view of the Inc.). This was followed by an incubation with horseradish peroxidase-conjugated conflicting reports on the importance of viral burden in neu- streptavidin (BioGenex) for 15 min at room temperature. Sections were washed in PBS (three times for 10 min each), developed with AEC as described above, ropathogenicity of both human immunodeficiency virus (1, 2, and counterstained with Mayer’s hematoxylin. 17, 21) and simian immunodeficiency virus (41, 43, 46, 48). In Immunohistochemical staining of glial fibrillary acidic protein (GFAP) was this study, we examined in more detail properties of the CNS performed on paraffin-embedded sections (4 mm). Sections were deparaffinized, infection by two of the neurovirulent viruses, Fr98 and Fr98/ rehydrated, and washed in PBS prior to incubation with rabbit anti-bovine GFAP SE, and the nonneurovirulent virus Fr54 in an effort to identify antiserum (Dakopatts) for1hat37°C. Sections were incubated with a biotinyl- ated goat anti-rabbit immunoglobulin (Vector) for 30 min at 37°C, followed by features of these infections that correlate with neurovirulence. an incubation with horseradish peroxidase-conjugated streptavidin (BioGenex) Surprisingly, no differences were found between the neuroviru- for 15 min at room temperature. Sections were developed with AEC as described lent and nonneurovirulent viruses with respect to the appear- above and counterstained with Mayer’s hematoxylin. ance of vacuolar degeneration, activation of astrocytes and Cell counts. Fresh, frozen brain tissue was sectioned (5 mm), and every eighth microglial cells, regional distribution of virus, or the cell types section was stained for viral envelope protein by using a polyclonal goat anti-gp70 infected in the brain. However, application of more quantita- antiserum as described above. The number of gp70-positive cells in the cerebella was determined in a total of five sections. From these five sections, the mean 6 tive measurements of viral protein expression in the brain standard deviation was determined for four mice per virus strain: Fr98/SE (52 to revealed viral burden to be a consistent correlate of neuroviru- 75 days postinoculation) and Fr54 (52 to 75 days postinoculation). The means 6 lence in this model. The results suggest that the neurovirulent standard errors of these two groups were compared by using the unpaired viruses differed from the nonneurovirulent virus in the extent two-tailed Student t test. of their spread among microglial cells after initial virus entry Double-label indirect immunofluorescence. Mice were anesthetized by inha- lation of methoxyfluorane and perfused with PBS followed by 0.5% paraformal- into the brain. dehyde-lysine-periodate fixative (PLP) (30). Vibratome sections (50 mm) of PLP-fixed brain were pretreated with 0.1% Triton X-100 for 5 min and then blocked with 5% bovine serum albumin for1hatroom temperature. Viral MATERIALS AND METHODS envelope protein and cell-specific markers were labeled sequentially. Sections were incubated with primary antibodies overnight at 4°C and then with secondary Viruses, animals, and clinical disease. The chimeric viruses were generated as antibodies at room temperature for 1 to 2 h. The sections were washed (three 9 previously described (19). Briefly, Fr98 and Fr54 contain the 3 pol and env times
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