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Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Multiple sclerosis (MS) is a CD4+ T cell-mediated autoimmune demyelinating disease affecting humans that has a suspected virus etiology (12). Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease serves as a relevant mouse model of MS due to numerous pathological and immunological similarities (13). Infection of susceptible SJL/J mice with the BeAn strain of TMEV results in a chronic progressive CD4+ T cell-mediated CNS demyelinating disease onsetting 30–35 days postinfection and characterized by persistent infection of CNS microglia (14). Myelin destruction is initiated by virus-specific CD4+ T cells that eventually lead to the activation of myelin-specific, autoreactive CD4+ T cells via epitope spreading, with responses to PLP139–151 first detected at 50 days postinfection (15, 16). Therefore, TMEV-induced demyelinating disease is a highly relevant model for studying virus-initiated autoimmune disease.
Recently, we developed a molecular mimicry model for initiation of autoimmune demyelination following virus infection with TMEV containing a self myelin epitope (11). Native or mimic sequences of the immunodominant PLP139–151 epitope were inserted into a nonpathogenic TMEV variant. Infection of SJL mice with TMEV encoding native mouse PLP139–151, an altered peptide ligand of PLP139–151, or a PLP139–151 mimic present in the protease IV protein of Hemophilus influenzae induced a rapid onset demyelinating disease associated with the induction of PLP139–151-specific CD4+ T cell responses. The current studies were conducted to determine whether the early onset demyelinating disease occurred directly through early activation of PLP139–151-specific CD4+ T cells. The results show that the PLP139–151-specific CD4+ T cells induced in PLP139-TMEV-infected mice were encephalitogenic, as demonstrated by serial transfer of these T cells to naive mice, and that infection of mice with PLP139-TMEV at sites peripheral to the CNS resulted in activation of PLP139–151-specific CD4+ T cells leading to CNS demyelination. Most compellingly, PLP139–151-specific tolerance induction before PLP139-TMEV infection resulted in reduced clinical demyelinating disease corresponding to a reduced PLP139–151-specific CD4+ T cell response. Collectively, these results demonstrate that infection with a virus expressing a self epitope mimic can directly induce autoreactive T cells with pathologic potential in the absence of CFA.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The cDNA encoding the BeAn strain of TMEV was modified to
contain a ClaI restriction site at bp 1137, resulting in the
deletion of 23 aa from the virus leader (designated 
Cla-BeAn), as
previously described (11). Briefly, PCR methods were used
to insert ClaI sites into PLP DNA at both ends of a 30-aa
piece, PLP130–159, which encompassed the encephalitogenic PLP139–151
epitope. This piece was then inserted into the ClaI site in
the ClaI BeAn virus cDNA. Viral RNA was produced from the
cDNA for each recombinant using a T7 promoter transcription kit (Roche
Molecular Biochemicals, Indianapolis, IN) and then transfected using
Lipofectin (Life Technologies, Rockville, MD) into BHK-21 cells
to produce infectious virus. BHK-21 cells were repeatedly infected with
virus in serum-free DMEM medium (Sigma-Aldrich, St. Louis, MO) until a
viral titer of 1 x 109 PFU/ml was obtained
for the viral construct.
Infection and clinical evaluation of mice
Five- to 6-wk-old female SJL mice were purchased from Harlan Labs (Bethesda, MD) and housed in the Northwestern University animal facility. Mice were infected by intracerebral (i.c.) injection with 3 x 107 PFU virus. Mice were scored at daily intervals on a clinical scale of 0–5: score 0, mice show no signs of disease; score 1, mice show mild gait abnormalities; score 2, mice show more severe gait abnormalities; score 3, mice had paralysis in one limb; score 4, mice had more than one paralyzed limb; score 5, mice were moribund.
Peptides
PLP139–151 (HSLGKWLGHPDKF), PLP178–191 (NTWTTCQSIAFPSK), VP2 70–86 (WTTSQEAFSHIRIPLPH), and OVA323–339 (ISQAVHAAHAEINEAGR) were purchased from Peptides International (Louisville, KY). The amino acid composition was verified by mass spectrometry, and purity was assessed by HPLC.
Delayed-type hypersensitivity response
Delayed-type hypersensitivity (DTH) assays were performed by injecting mice s.c. with 5 µg challenge peptide, PLP139–151 or VP2 70–86, into the ears. The ear thickness was determined before injection using a Mitutoyo model 7326 engineers micrometer (Schlesinger’s Tools, Brooklyn, NY). After 24 h, the ears were again measured, and differences in ear swelling over prechallenge thickness were expressed in units of 10-4 inches ± SEM.
T cell proliferation and cytokine assays
Spleens were removed from infected mice at various times
following infection. Splenocytes were cultured at 1 x
106 cells/well (in 96-well microtiter plates) in
HL-1 medium (BioWhittaker, Walkersville, MD) supplemented with 2 mM
L-glutamine, 100 U/ml penicillin, and 100 µg/ml
streptomycin. Peptides were added to the wells at increasing
concentrations from 1 to 100 µM. Plates were incubated at 37°C for
72 h and then pulsed with 1 µCi [3H]TdR
for 24 h before harvesting and counting. Proliferation was
determined with triplicate wells for each peptide concentration and
then expressed as cpm ± SEM. The stimulation index (SI) was
calculated by dividing cpm in experimental wells by the cpm in
PBS-containing wells. For cytokine analysis, a duplicate set of
proliferation wells was used to collect supernatants at 48 and 72
h. Supernatants were analyzed for IL-2, IFN-
, or IL-5 secretion by
ELISA (Endogen, Cambridge, MA).
Coupled cell tolerance
Spleens were removed from naive mice and mechanically disrupted, and the RBCs were lysed. The splenocytes were incubated with ethylcarbodiimide (150 mg/ 3.2 x 108 cells) and peptide (1 mg/ml PLP139–151 or OVA 323–339) on ice, shaking periodically for 2 h. The coupled cells were washed and centrifuged to remove cell clumps. The single cell suspension was resuspended in BSS, and 5 x 107 coupled cells were injected i.v. into each recipient mouse. Recipient mice were given peptide-coupled splenocytes at day 7 before infection and again at day 3 following infection with PLP139-TMEV virus.
Serial disease transfer
Female SJL mice 5–6 wk old were infected with PLP139-TMEV virus, as described above. At 21 days postinfection, spleens were removed from the mice and mechanically disrupted, and the RBCs were lysed. The resulting splenocytes were cultured with 20 µg/ml peptide (PLP139–151 or VP2 70–86) for 4 days in DMEM supplemented with 10% FCS, 0.1 mM nonessential amino acids, 2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, and 5.5 µM 2-ME. After the incubation, some of the cells were incubated with anti-CD4-coated MACS beads (Miltenyi Biotec, Auburn, CA), and then sorted on the AutoMacs (Miltenyi Biotec) column to separate out the CD4+ T cells. Both the whole splenocytes and the sorted T cells were washed and resuspended in BSS. Then 3 x 106 blast cells were transferred i.v. to each mouse.
Viral plaque assay
The brains and spinal cords were removed from the infected mice at the indicated days postinfection. The organs were homogenized and then diluted in serum-free DMEM for the assay. BHK-21 cells were seeded in tissue culture dishes for 2 days and grown to confluency. The cells were washed with serum-free DMEM before the addition of the homogenized tissue dilutions. The cells were then incubated at room temperature for 1 h with occasional swirling. A 2% agar solution was added in equal volume to 2x DMEM supplemented with 2% serum, plus 5 mM L-glutamine, 200 µg/ml penicillin, and 200 µg/ml streptomycin. Following a 1-h incubation, the DMEM/agar mixture was added to the cells, and the cells were incubated at 34°C for 6 days in a humidified environment, at which time the agar layer was removed from the cells. The cells were fixed with methanol, and then stained with crystal violet solution (0.12% crystal violet in 20% ethanol). The plaques were counted on each plate and multiplied by the dilution and the amount of homogenate added to the plate to determine the PFU/ml. The weight of the tissue (mg)/ml homogenate was then used to calculate PFU/mg.
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Results |
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Intracerebral injection of mice with the wild-type (WT) BeAn
strain of TMEV leads to the development of a chronic progressive
demyelinating disease with clinical signs appearing 
30–40 days
postinfection (Fig. 1
). A nonpathogenic
variant of the BeAn virus, Cla BeAn, was constructed by removing a
23-aa coding region from the leader sequence and inserting a
ClaI restriction digest site into which the immunodominant
myelin epitope PLP139–151 was then inserted to produce PLP139-TMEV
(11). Mice infected with PLP139-TMEV developed an earlier
onset severe demyelinating disease compared with WT TMEV-infected
mice (Fig. 1). As a control, a virus was constructed with an irrelevant
epitope OVA323–339 inserted into the Cla BeAn
virus, and mice infected with this virus developed a late onset
demyelinating disease similar to the WT BeAn virus.
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Serial transfer experiments were conducted to determine whether
infection with PLP139-TMEV virus in the absence of CFA induces the
differentiation of encephalitogenic PLP139–151-specific
CD4+ T cells. Previous studies have demonstrated
that PLP139–151-specific CD4+ T cells isolated
from spleens of mice immunized with PLP139–151/CFA can transfer
experimental autoimmune encephalomyelitis (EAE) to naive recipient mice
(17). Splenocytes from SJL mice 21 days postinfection with
PLP139-TMEV were reactivated in vitro with either PLP139–151 peptide
or viral peptide, VP2 70–86, as a control. One group of
PLP139–151-reactivated splenocytes was magnetically sorted to isolate
CD4+ T cells. Peptide-activated splenocytes or
sorted CD4+ T cells were transferred i.v. to
naive mice. Mice that received the PLP139–151-reactivated splenocytes
developed clinical signs of demyelinating disease onsetting 10 days
posttransfer (Fig. 2, A and
B). However, mice that received VP2 70–86-activated
splenocytes did not develop demyelinating disease, despite the fact VP2
70–86-reactive cells are found in the spleens of PLP139-TMEV-infected
mice (11). Furthermore, purified PLP139–151-reactivated
splenic CD4+ T cells also were able to transfer
disease to naive mice similar to the PLP139–151-reactivated
splenocytes. Meanwhile, the reactivated splenocytes that were not
CD4+ (those remaining after the
CD4+ purification) were unable to transfer
disease to naive recipients (data not shown). Next, the
CD4+ T cell responses were examined in the
transfer recipients (Fig. 3). Mice that
received the PLP139–151-reactivated splenocytes or
CD4+ T cells displayed specific
CD4+ T cell responses to PLP139–151, but not to
virus peptide. Therefore, PLP139–151-specific
CD4+ T cells that arise during infection with
PLP139-TMEV virus can directly mediate demyelinating disease. These
experiments demonstrated that infection with a virus that encodes a
self epitope directly activates self-reactive
CD4+ T cells with the potential to initiate an
autoimmune disease.
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PLP139-TMEV virus administered directly to the CNS, via i.c.
injection, results in demyelinating disease in the CNS. In an attempt
to determine whether local CNS inflammation at disease initiation was a
prerequisite for the development of virus-induced molecular mimicry, we
asked whether PLP139–151-specific CD4+ T cells
and clinical disease could be activated by PLP139-TMEV infection at
sites peripheral to the CNS. SJL mice were infected with PLP139-TMEV
virus via i.v., i.p., and s.c. routes and followed for development of
clinical disease signs. As shown in Fig. 4, SJL mice infected at peripheral sites
developed early onset demyelinating disease with similar incidence of
disease and kinetics as by the i.c. route, but with slightly reduced
severity. Therefore, infection with epitope mimic PLP139-TMEV virus at
sites peripheral to the CNS target organ leads to development of
organ-specific autoimmune disease.
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). Mice infected by
all the different routes of infection developed significant
CD4+ T cell responses to the major viral epitope,
VP2 70–86, and to PLP139–151 by 14 days postinfection. Interestingly,
proliferative responses in the mice infected by the peripheral routes,
particularly i.v., were somewhat higher than those in mice infected by
the i.c. route (Fig. 5A). This same pattern was observed
when CD4+ T cells were analyzed for secretion of
the Th1 cytokines, IFN- and IL-2, in response to viral and myelin
epitopes at 14 days postinfection (Fig. 6). Splenic proliferative and cytokine
responses to both VP2 70–86 and PLP139–151 persisted in all groups at
28 and 56 days postinfection. Responses in mice infected by the i.v.
route remained greater than the other routes at later times
postinfection. Mice infected with PLP139-TMEV virus by the various
routes did not result in induction of CD4+ T
cells that secreted IL-4 or IL-5 in response to either viral or myelin
peptides (data not shown). These results suggest that infection with
the mimic virus at sites peripheral to the CNS can activate
CD4+ Th1-type T cells in the periphery, resulting
in the development of autoimmune demyelinating disease in the
CNS.
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However, the virus loads in the mice infected by the peripheral routes
were significantly lower than those in the brains and spinal cords from
mice infected i.c. with PLP139-TMEV, which had similar virus load as WT
BeAn-infected mice. Therefore, PLP139-TMEV mimic virus can spread to
the CNS in mice infected at sites peripheral to the CNS, but at
significantly reduced levels compared with mice infected in the CNS,
even though the severity of the disease course in mice infected by the
peripheral and CNS routes is similar. This suggests that the rapid
onset CNS disease is primarily due to the ability of infection with
PLP139-TMEV by the various routes to activate a peripheral
PLP139–151-specific CD4+ T cell response that
then mediates CNS myelin destruction.
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The data to this point show that PLP139-TMEV infection induces the
peripheral activation of PLP139–151-specific T cells with pathologic
potential following in vitro reactivation. To directly determine
whether the early onset demyelinating disease was a direct result of
the activation of PLP139–151-specific CD4+ T
cells arising via molecular mimicry, the effects of
PLP139–151-specific tolerance on disease induction in mice infected
with the PLP139-TMEV virus were determined. We have previously reported
that tolerance induced with splenocytes pulsed with PLP139–151 and
fixed with ethylcarbodiimide (PLP139–151-splenocyte (SP)) is an
effective means to prevent development of PLP139–151/CFA-induced R-EAE
in SJL mice (18). Previous studies also showed that
coupled cell tolerance developed independent of
CD8+ T cells; thus, PLP139–151-specific
tolerance was CD4+ T cell dependent
(19). Groups of 10 SJL mice were tolerized by the i.v.
injection of 5 x 107 PLP139–151-SP or
OVA323–339-SP (as a control) 7 days before and again 3
days after infection with PLP139-TMEV virus. PLP139–151 tolerant mice
displayed a significantly reduced disease severity (Fig. 7A) and a lower incidence of
disease (Fig. 7B) compared with control
OVA323–339-tolerized mice and with mice that received no
tolerance treatment.
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PLP139–151-tolerized mice exhibited normal CD4+
T cell-specific responses to VP2 70–86, but significantly reduced
responses to PLP139–151 at early as well as at later times
post-PLP139-TMEV infection. In contrast, mice tolerized to control
OVA323–339 peptide developed CD4+ T
cell-specific responses to both VP2 70–86 and PLP139–151 similar to
untreated mice. Similarly, PLP139–151-, but not VP2 70–86-induced Th1
(IL-2 and IFN-) cytokine responses were inhibited in
PLP139–151-SP-tolerized mice (Fig. 9).
These results directly demonstrate that the early demyelinating disease
in mice infected with PLP139-TMEV virus is dependent on the
PLP139–151-specific CD4+ Th1 responses, as
demonstrated by specifically reduced PLP139–151-specific
CD4+ T cell responses accompanied by reduced
demyelinating disease in PLP139–151-tolerized mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Organ-specific autoimmune diseases have been strongly suggested to be initiated and/or exacerbated by virus infection (1). The possible mechanisms by which virus infection can trigger an autoimmune response include molecular mimicry, bystander activation, and epitope spreading. Molecular mimicry involves the de novo activation of autoreactive T cells due to the cross-reactivity between self epitopes and viral epitopes during a virus infection (2). Bystander activation is the nonspecific activation of autoreactive T cells resulting from the direct inflammatory and/or necrotic effects of virus infection on tissue in the target organ (20). Epitope spreading is the activation of autoreactive T cells due to the tissue damage following virus infection releasing self epitopes as a result of the immune response to an organ-localized persistent virus infection (15, 21).
Molecular mimicry theoretically results from infection with a virus expressing a peptide determinant(s) that shares homology with a self peptide, resulting in activation of T cells that can cross-react with the self epitope. TCR degeneracy has been ascribed as the reason for recognition of multiple peptides by the same TCR. Recent studies have shown degeneracy in the TCR specific for the human myelin basic protein MBP85–99 peptide, with the TCR requiring only a few critical residues for recognition (22). T cell clones specific for MBP85–99 established from MS patients were shown to cross-react with viral peptides expressed by a number of viruses, including HSV, adenovirus, reovirus, and human papillomavirus (5). Likewise, a few critical residues were shown to be necessary for recognition of PLP139–151 by its TCR (23, 24). PLP139–151-specific T cell hybridomas derived from SJL mice were also shown to cross-react with peptides expressed by various mouse pathogens, demonstrating degeneracy in the PLP139–151 TCR (25). Therefore, myelin-specific T cells have been shown by in vitro studies to have the potential to cross-react with viral epitopes, supporting the molecular mimicry model described in these studies.
EAE is a well-established experimental model for studying self myelin peptide-induced autoimmune demyelinating disease. PLP139–151/CFA immunization of SJL mice results in a relapsing-remitting demyelinating disease mediated in the initial phase by PLP139–151-specific CD4+ Th1-type T cells with the following relapses mediated by myelin-specific Th1 cells specific for endogenous myelin epitopes such as PLP178–191 and MBP84–104 activated via epitope spreading (18, 21, 26). The pathologic significance of epitope spreading is illustrated by the finding that tolerance to PLP178–191, but not to PLP139–151, is required to prevent disease relapses in mice treated following recovery from acute disease (18). Additionally, PLP139–151-specific CD4+ T cells from the immunized mice are encephalitogenic and can transfer disease to naive recipient mice (18, 27). However, induction of EAE initiated by either the native mouse myelin peptides or mimic peptides requires the presence of CFA to induce this hierarchical cascade of peptide-specific autoimmune responses. CFA creates an artificial inflammatory milieu that does not reflect the natural environment in which self or mimic peptides would be normally encountered; thus, an infectious model as described in the current studies is more appropriate for the study of molecular mimicry.
TMEV is a natural mouse pathogen that upon infection can lead to the
development of an autoimmune demyelinating disease in which the chronic
phase of disease is mediated by myelin-specific
CD4+ Th1 cells (21, 28). Previous
studies have shown that the development of autoimmune demyelinating
disease is dependent on persistent virus infection of the CNS,
predominantly in microglial cells (29). Initially
following infection with the WT BeAn strain of TMEV, mice display
CD4+ T cell responses only to virus Ags; however,
beginning 50 days postinfection, CD4+ T cell
responses to immunodominant PLP139–151 myelin epitope develop.
Subsequently, as the disease progresses, epitope spreading leads to
development of CD4+ T cell responses to a variety
of additional myelin epitopes (15). Furthermore, the
demyelinating disease develops independent of MHC class I presentation
to CD8+ T cells (30). Tolerance to
intact TMEV virions coupled to syngeneic splenocytes before TMEV
infection anergizes virus-specific CD4+ T cell
responses, resulting in a reduction of incidence and severity of
demyelinating disease (31, 32). In contrast, induction of
peripheral tolerance to mouse spinal cord homogenate before TMEV
infection did not affect the initiation of TMEV-induced clinical
disease and had no effect on the development of virus-specific
CD4+ T cell responses (33).
Together, these studies indicate that the initial virus-specific T cell
response and continued response to persistent virus infection are
critical for the activation of the myelin-specific
CD4+ T cell response and the development of the
chronic progressive autoimmune demyelinating disease.
Recently, our laboratory developed a virus-induced model of molecular
mimicry for the induction of autoimmune demyelinating disease
(11). A nonpathogenic TMEV variant
(ClaI-BeAn) was used to construct a virus that contained
a self myelin sequence, PLP130–159, within the virus coding region.
Mice infected with this virus developed an early onset autoimmune
demyelinating disease as well as displaying early
CD4+ T cell responses to both TMEV epitopes and
PLP139–151, unlike infection with WT TMEV, in which early T cell
responses are only seen in response to virus epitopes. In addition,
mimic PLP139–151 sequences were constructed in which amino acid
substitutions were made at the primary (aa 144) or secondary (aa 147)
TCR contact residues. Infection with the virus carrying a substitution
in the secondary TCR contact residue induced early onset demyelinating
disease and activated cross-reactive PLP139–151-specific
CD4+ T cells. In contrast, infection with the
virus substituted at the primary TCR contact residue (position 144)
failed to induce early demyelinating disease or activation of
cross-reactive PLP139–151-specific CD4+ T cells.
An additional mimic virus was constructed by inserting a sequence from
H. influenzae that shared only 6 of 13 aa with the core
PLP139–151 epitope (11). More significant to a role for
molecular mimicry in induction of autoimmune disease, infection with
this mimic virus resulted in early onset demyelinating disease and
activation of Th1 cells cross-reactive with the native PLP139–151
determinant. This model is the first to directly demonstrate that a
virus encoding a mimic of an encephalitogenic self myelin epitope could
induce an autoreactive CD4+ T cell response
leading to a CNS demyelinating disease.
As illustrated by the ability of PLP139–151-specific
CD4+ T cells recovered from PLP139-TMEV-infected
mice to transfer disease to naive recipients and by the ability of
peptide-specific tolerance to inhibit induction of PLP139-TMEV-induced
disease, the current results clearly demonstrate that the early onset
demyelinating disease is due to the activity of the autoreactive
PLP139–151-specific Th1 cells and not due to any direct or indirect
effects of the virus infection. The failure of splenic T cells
reactivated in vitro with VP2 70–86 to transfer disease (Fig. 2
) also
indicates there is no cross-reactivity between the immunodominant TMEV
epitope and any myelin epitopes. Our previous report (11)
showed that insertion of even a nonself epitope (OVA317–346) into the
nonpathogenic TMEV parental virus led to a late onset (50 days
postinfection) disease, indicating that reintroduction of nonspecific
30 mer into the leader of the ClaI-BeAn parental strain
restored the ability of the virus to persist in vivo. Mice infected
with OVA323-TMEV displayed CD4+ T cell responses
to VP2 70–86 within 14 days postinfection, but developed demonstrable
PLP139–151-specific CD4+ T cell responses only
at later times (
90 days postinfection). Nevertheless, the current
studies were critical in definitively ascribing the early onset disease
to the activity of the autoreactive PLP139–151-specific T cell
population and effectively rule out a role for T cells directed against
virus epitopes. It is also significant that our results indicate that
demyelinating disease can be induced in animals infected with
PLP139-TMEV by various peripheral routes. This suggests that
peripheral infection with a mimic encoding virus is sufficient to
activate autoreactive T cells that can traffic to the CNS and initiate
disease. Thus, local CNS inflammation, induced either as a result of
injection trauma and/or by direct virus infection of glial cells, may
not be a required cofactor for induction of autoimmunity via molecular
mimicry.
In summary, these studies provide direct evidence that TMEV encoding PLP139–151 causes early onset CNS demyelinating disease due to the direct activation of autoreactive T cells. Using appropriate HLA-DR and human TCR transgenic mice (34), this model system should allow the functional identification of pathogen-encoded mimic epitopes for a variety of human myelin proteins that may be involved in the pathogenesis of MS. A final advantage of the TMEV molecular mimicry model that inserts 30 mers into the virus coding region is that induction of the autoimmune disease will require that the mimic epitope be processed from its native flanking regions in addition to the requirement that the core epitope be presented in an appropriate fashion to activate the self-reactive Th1 response.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Stephen D. Miller, Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611. E-mail address: s-d-miller{at}northwestern.edu
3 Abbreviations used in this paper: PLP, proteolipid protein; DTH, delayed-type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; i.c., intracerebral; MBP, myelin basic protein; MS, multiple sclerosis; SI, stimulation index; SP, splenocyte; TMEV, Theiler’s murine encephalomyelitis virus; WT, wild type.
Received for publication March 22, 2002. Accepted for publication June 20, 2002.
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