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-Herpesvirus Infection1
Trudeau Institute, Saranac Lake, NY 12983
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-herpesviruses, EBV and Kaposi’s sarcoma-associated
herpesvirus, establish life-long latency and can reactivate in
immunocompromised individuals. T cells play an important role in
controlling persistent EBV infection, whereas a role for humoral
immunity is less clear. The murine -herpesvirus-68 has biological
and structural similarities to the human -herpesviruses, and
provides an important in vivo experimental model for dissecting
mechanisms of immune control. In the current studies,
CD28-/- mice were used to address the role of Abs in
control of persistent murine -herpesvirus-68 infection. Lytic
infection was controlled in the lungs of CD28-/- mice,
and latency was maintained in B cells at normal frequencies. Although
class-switched virus-specific Abs were initially generated in the
absence of germinal centers, titers and viral neutralizing activity
rapidly waned. T cell depletion in CD28-/- mice with
compromised Ab responses, but not in control mice with intact Ab
responses, resulted in significant recrudescence from latency, both in
the spleen and the lung. Recrudescence could be prevented by passive
transfer of immune serum. These data directly demonstrate an important
contribution of humoral immunity to control of -herpesvirus latency,
and have significant implications for clinical
intervention. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-herpesviruses, EBV and Kaposi’s sarcoma-associated
herpesvirus, are persistent pathogens that establish life-long
latency, mainly in B lymphocytes. In immunocompetent individuals, the
virus is maintained in a quiescent state through immune mechanisms of
control. However, in immunocompromised individuals, for example, as a
consequence of posttransplant immunosuppression or AIDS, loss of immune
control is associated with the onset of lymphoproliferative disorders
and various malignancies. Thus, understanding the immune control of
-herpesvirus latency is a major health priority. Immune control of
human -herpesviruses is thought to be predominantly mediated by
CD8+ T cells (1, 2), and adoptive
immunotherapy with EBV-specific cytotoxic T cells following bone marrow
transplantation reduces the risk of developing posttransplant
EBV-associated lymphoproliferative disease and lymphomas
(3). In contrast to the well-established role of
cell-mediated immunity, little information is available regarding the
contribution of Ab to controlling persistent -herpesvirus
infection.
Murine -herpesvirus-68
(MHV-68)3 is a natural
pathogen of rodents that provides an easily manipulated small animal
model for studying general mechanisms of immune control of
-herpesviruses. The virus has significant biological and structural
similarities to the human -herpesviruses (4, 5) and is
emerging as an important experimental model for studying mechanisms of
-herpesvirus-induced pathology and basic mechanisms of immune
control of -herpesviruses (6, 7, 8, 9, 10). Intranasal infection
with MHV-68 establishes an acute viral infection in the lungs. Although
the lytic virus is rapidly cleared, largely by
CD8+ T cells, the virus is thought to disseminate
from the lung, and latency is established (11). Similar to
the human -herpesviruses, B cells are a major reservoir of latent
virus, although macrophages, dendritic cells and lung epithelial cells
can also be latently infected (11, 12, 13, 14). Both
CD4+ T cells and CD8+ T
cells are important in the immune control of latency (reviewed in Ref.
9).
Despite the importance of T cells in controlling MHV-68 infection, T cell depletion of latently infected mice does not result in viral recrudescence, indirectly suggesting a role for virus-specific Ab (11, 15). Following MHV-68 infection, there is a strong nonspecific Ab response, closely followed by a virus-specific Ab response (16, 17). The possibility that Abs participate in immune control of the latent stages of infection was supported by experiments showing that T cell depletion of B cell-deficient µMT mice, but not control C57BL/6 (B6) mice, allowed viral recrudescence in the lung (11, 18). The goal of the current studies was to directly assess the contribution of virus-specific Abs in the immune control of latent MHV-68. Because B cells are an important reservoir of latency (12, 14), and also play an important role in disseminating virus in the host (11) and in controlling reactivation from latency (19), analysis of Ab-mediated immune control of latency must be conducted in mice with normal B cells, to allow the development of normal reservoirs of latency, but with no anti-viral Abs. We show that CD28-deficient (CD28-/-) mice provide a suitable model. CD28 is a costimulatory molecule important in T-B collaboration (reviewed in Ref. 20). CD28-/- mice have normal levels of CD4+ and CD8+ T and B cells (21), but have deficient humoral immunity (21, 22). CD28-/- mice have been shown to be capable of controlling some, but not all, viral infections (21, 22, 23, 24, 25, 26, 27). Our laboratory previously reported that CD28-/- mice established MHV-68 latency in B cells although at reduced levels compared with B6 mice, correlating with decreased numbers of peanut agglutinin (PNA)high germinal center B cells, which we showed to be a preferential reservoir for latency (14). Therefore, CD28-/- mice provide a relevant model for examining the role of humoral immunity in controlling MHV-68 latency.
The current analysis of MHV-68-infected CD28-/- mice showed that the mice controlled the initial lytic infection, established normal reservoirs of latency, including B cells, and exhibited normal long-term immune control of latency, yet had a defective Ab response. Importantly, upon T cell depletion, Ab-deficient CD28-/- mice, but not B6 mice, lost immune control of latency in the lung and spleen, indicated by recrudescence of lytic virus. Prevention of viral recrudescence after passive transfer of immune serum directly demonstrated a role for virus-specific Ab in immune control of MHV-68 latency.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J (B6) and C57BL/6-CD28tm1Mak (CD28-/-) (21) mice were bred at the Trudeau Institute (Saranac Lake, NY) or purchased from The Jackson Laboratory (Bar Harbor, ME). Six- to 8-wk-old male and female mice were housed under specific pathogen-free conditions in BL3 containment for the experimental period. All animal procedures in these experiments were approved by the Institutional Animal Care and Use Committee at the Trudeau Institute. CD28-/- mice received sulfamethoxazole and trimethoprim (GensiaSicor Pharmaceuticals, Irvine, CA) treated water throughout the study to prevent opportunistic infection by Pneumocystis carinii (28).
Virus
MHV-68 (WUMS strain) was obtained from S. Virgin (University of Washington, St. Louis, MO) and propagated in NIH 3T3 cells. Virus titer was determined by plaque assay on NIH 3T3 cells as described (6). Mice were anesthetized with 2,2,2-tribromoethanol and intranasally infected with 400 PFU of the virus. Control mice were infected with 300 50% egg infectious doses of influenza A virus (A/HKx31), as described (29).
Immunohistochemistry
Spleens were imbedded in Optimum Cutting Temperature compound (Miles, Elkhart, IN) and snap frozen in liquid nitrogen. Serial sections (6 µm) were incubated with anti-mouse B220/CD45RB Ab (RA3-6B2; BD PharMingen, San Diego, CA) or PNA-conjugated with biotin (Vector Laboratories, Birmingham, CA). Subsequently, the sections were incubated with the avidin/biotin peroxidase complex, and then incubated with 3,3'-diaminobenzidine substrate (Vector Laboratories). Sections were counterstained with H&E.
Virus-specific Ab assays
Virus-specific Ab titer was determined by ELISA (17). Sera from naive or influenza virus-infected mice were included as negative controls. Neutralizing activity was determined as described (16), except dilutions of serum were incubated with 100 PFU MHV-68 for 90 min and were cultured with NIH 3T3 cells for 6 days. The neutralizing titer refers to the highest dilution of serum that reduced the number of plaques by 50%.
Assays for virus-specific T cells
Virus-specific T cells were analyzed on a FACScan after staining
with PE-conjugated tetrameric reagents, open reading frame (ORF)
6487–495/Db and
ORF61524–531/Kb, obtained
from the Trudeau Institute Molecular Core Facility, and subsequently
with CD62 ligand-FITC and CD8-TriColor. IFN- secretion of
CD4+ and CD8+ T cells were
assessed in response to APCs pulsed with virus or
virus-specific peptides, ORF6487–495
(AGPHNCMEI) and ORF61524–531
(TSINFVKI) (30, 31).
Infective center assay
Infective center assays were performed as described (32). Briefly, serial dilutions of splenocytes or lung homogenates were plated onto monolayers of NIH 3T3 cells and overlaid with carboxymethyl cellulose. After 6 days of culture, cells were fixed and stained with Giemsa (Sigma-Aldrich, St. Louis, MO). As this assay measures lytic virus as well as reactivable latent virus, samples were simultaneously assayed after a single freeze/thaw cycle to assess the contribution of lytic virus to the titers. Previous controls have shown that a single freeze/thaw cycle does not result in the loss of lytic virus (33). Reactivable latent virus levels in individual mice were calculated by subtracting virus levels of the freeze/thaw sample from virus levels of the duplicate untreated sample.
Limiting dilution-nested DNA PCR
Splenocytes were stained with Ab against CD4/CD8-FITC and CD19-PE, (BD PharMingen) and propidium iodide (Sigma-Aldrich). The viable (propidium iodide-low) lymphocyte population was gated and CD19+ cells were FACS-sorted to a purity of >99%. To determine the frequency of latency in purified B cells, nested PCR was performed on serial dilutions of B cells, and frequencies were determined by Poisson distribution, as described (13, 19, 34). As controls of nested PCR, 104 NIH 3T3 cells/well with and without plasmid DNA containing the MHV-68 ORF50 gene were included in each 96-well PCR assay. As preformed lytic virus was undetectable in the spleens of B6 and CD28-/- mice by infective center assay after day 35 postinfection, genome-positive cells assessed after this time were considered to be latently infected.
In vivo T cell depletion
Mice were injected i.p. with 250 µg purified anti-Thy1.2
(30H12), anti-CD4 (GK1.5), anti-CD8 (TIB210), or
isotype-matched control Ab (Rat IgG2b, LTF2) from ascites or
concentrated culture supernatant at 2–3 day intervals for 14–21 days,
beginning 
60 days postinfection. To confirm T cell depletion,
splenocytes were stained with anti-CD4 or anti-CD8 Abs or
MHV-68 tetramers. The postdepletion levels of
CD4+ and CD8+ T cells were
<1% of total spleen cells and virus-specific memory T cells were
undetectable.
Passive transfer of immune serum
Immune sera were obtained from MHV-68-infected B6 mice 28–35 days postinfection. Neutralizing Ab and MHV-68 specific-IgG levels were determined and the protective effect of the immune sera against MHV-68 infection was tested in naive B6 mice (data not shown). CD28-/- and B6 mice were administered 2.5 ml immune sera i.p. in 0.5 ml doses at 8-h intervals, as described (35). Immune serum from influenza A-infected mice was administered as a control. One day after the final injection of immune sera, in vivo T cell depletion was initiated.
Statistical analysis
ELISA titers of MHV-68-specific Abs were analyzed by the Mann-Whitney Sum test. Significant differences (p < 0.05) in the number of virus-specific T cells between CD28-/- and B6 mice were determined by a two-tailed Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been shown that the costimulatory requirements for
anti-viral CTL responses depend on the properties of the virus. For
example, CD28-/- mice effectively control
lymphocytic choriomeningitis virus, but fail to control vesicular
stomatitis virus and influenza virus (21, 22, 23, 24, 25, 27). To
determine whether CD28-/- mice could
effectively control acute MHV-68 infection, mice were infected
intranasally with virus, and lytic viral load in the lung was followed.
Although the peak viral titers were higher and the kinetics of
clearance were delayed (2 days) compared with B6 control mice,
CD28-/- mice effectively cleared lytic virus
(Fig. 1
A). There was no
evidence for viral recrudescence in the lung at timepoints up to 150
days postinfection (data not shown).
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B). As
this assay can also detect lytic virus, the inability to detect
recrudescent lytic virus at later timepoints is another indication that
latency is controlled in the spleens of CD28-/-
mice. Second, we determined the frequency of latently infected splenic
B cells in the long-term by a limiting dilution/PCR assay. In this
assay the frequency of latently infected cells is assessed by the
presence of viral genome in the absence of preformed infectious virus
(36). The data show that the reservoirs of long-term
latency in splenic B cells in B6 and CD28-/-
mice are entirely comparable (Fig. 1C). Both the infective
center and limiting dilution/PCR assays showed that initial levels of
latency were reduced 10-fold in CD28-/-
mice, as we previously described (14), likely a
consequence of reduced numbers of activated germinal center B cells,
which harbor the highest frequency of latency early after
infection.
The virus-specific T cell response was also assessed in terms of
numbers of virus-specific T cells and IFN- secretion. There were
comparable numbers of T cells specific for two MHV-68 MHC class I
epitopes, ORF6487–495/Db
and ORF61524–531/Kb,
assessed by tetramer staining, in the spleens (Fig. 2A) and lungs (data not shown)
of MHV-68-infected CD28-/- and control mice. In
addition, virus-specific CD4+ and
CD8+ T cell effector function was assessed by an
IFN- ELISPOT assay (Fig. 2B). The data show that the
virus-specific CD8+ T cell numbers and IFN-
responses are relatively normal in the CD28-/-
mice. CD4+ T cells from
CD28-/- mice were functional, although the
magnitude of the IFN- response was reduced at all timepoints
measured. Taken together, the clearance of lytic virus, the absence of
viral recrudescence, the comparable frequencies of latently infected
cells, and the relatively normal numbers and function of virus-specific
T cells are consistent with efficient T cell immune control of MHV-68
in CD28-/- mice.
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It has been reported that CD28-/- mice do
not form germinal centers, due to the absence of T-B interactions
(37). However, because an early feature of MHV-68
infection is activation of both B and T cells (38), it is
formally possible that the virus overcomes the requirement for
CD28-mediated T-B interactions in the formation of germinal centers. B
and T cell activation appeared to be relatively intact in
CD28-/- mice, as our previous analysis showed
that splenomegaly and T cell lymphocytosis of the peripheral blood are
comparable to that observed in B6 mice (Flaño et al., Ref.
14 ; data not shown). Therefore, we examined spleen
sections for germinal center formation after MHV-68 infection. Although
PNA+ clusters were found scattered in the splenic
red pulp in CD28-/- mice after viral infection
(Fig. 3) there was no evidence for the
formal architecture of germinal centers. Thus, despite comparable
MHV-68-induced activation of both B and T cells, the viral infection
did not overcome the inability of CD28-/- mice
to form germinal centers.
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A) and, despite the absence
of germinal center formation in the CD28-/-
mice (37), the levels of virus-specific IgG Abs were
comparable in B6 and CD28-/- mice when measured
28 days after infection (Fig. 4B). However, the titers of
MHV-68-specific class-switched Abs (Fig. 4B), but not
MHV-68-specific IgM Abs (Fig. 4A) waned rapidly with time in
CD28-/- mice, whereas the titers of
MHV-68-specific class-switched Abs were sustained at high levels in B6
mice (Fig. 4B). In addition, the Abs in
CD28-/- mice were poorly neutralizing (Fig. 4C). Thus, the Ab response to MHV-68 is profoundly impaired
in CD28-/- mice.
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Our findings that CD28-/- mice have normal
reservoirs of B cell latency, effective T cell immune control, but
defective humoral immunity to MHV-68, confirmed that they are a
suitable model for directly examining the contribution of humoral
immunity in the control of -herpesvirus latency. Thus, we depleted T
cells from MHV-68-infected mice by i.p. injection of anti-Thy1.2
mAb. We initiated T cell depletion 60 days postinfection, at a time
when there was no neutralizing Ab (Fig. 4C), and monitored
levels of lytic virus in the lungs and spleens 2 wk later. The analysis
showed recrudescence of lytic virus in both the lungs (Fig. 5A) and spleens (Fig. 5B) of Ab-deficient CD28-/- mice,
but not control mice. These data strongly support the possibility that
humoral immunity contributes to the control of MHV-68 latency. T cell
depletion also resulted in a striking increase in latent virus in the
spleens of CD28-/- mice, and to a lesser
extent, in the spleens of B6 mice, as determined by the infective
center in vitro reactivation assay (Fig. 5C).
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A) and none in the spleen
(Fig. 6B) following depletion of either
CD4+ or CD8+ T cells,
whereas depletion of both subsets resulted in recrudescence of lytic
virus in the lung and spleen of CD28-/- mice.
In addition, depletion of both subsets of T cells was also required for
loss of control of latently infected spleen cells capable of in vitro
reactivation in Ab-deficient mice (Fig. 6C).
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To directly demonstrate a role for Ab in the immune control of
-herpesvirus latency, MHV-68 immune serum was obtained from latently
infected B6 mice and passively transferred into
CD28-/- mice, just before initiation of the T
cell depletion regimen. Influenza A virus-specific immune serum was
transferred to a separate cohort of mice as a specificity control.
Consistent with a role for Ab in controlling persistent virus, the data
show that transfer of MHV-68 immune serum, but not the irrelevant
serum, prevented the recrudescence of lytic virus in the lung (Fig. 7A) and spleen (Fig. 7B) of T cell-depleted MHV-68-infected
CD28-/- mice. Consistent with a role for T
cells in controlling reactivation from latency independent of Ab,
transfer of immune serum did not prevent the increase of latently
infected spleen cells capable of in vitro reactivation (Fig. 7C). Analysis of the MHV-68-specific Ab titers in
CD28-/- mice into which immune serum had been
transferred confirmed that the Ab transfer had reconstituted normal
levels of MHV-68-specific IgG (Fig. 7D) and that the
transferred immune serum restored the neutralizing titers to levels
comparable to those of MHV-68-infected B6 mice (Fig. 7E).
These data directly demonstrate a role for humoral immunity in the
control of -herpesvirus latency.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-herpesvirus
infection. Thus, T cell-depletion of CD28-/-
mice with impaired anti-viral Abs, but not control B6 mice with
intact humoral immunity, resulted in viral recrudescence in the spleen
and lungs. A direct role for protective Abs was demonstrated by the
ability of passively transferred immune serum to prevent viral
recrudescence in CD28-/- mice after T cell
depletion.
The data suggest that virus-specific Abs and immune T cells play
complementary roles in preventing viral recrudescence, as deficiency in
both cellular and humoral immunity was necessary to allow recrudescence
of lytic virus. For example, neither T cell-depleted B6 mice with
intact humoral immunity nor CD28-/- mice with
functional T cell immunity but no anti-viral Abs, showed evidence
of recrudescent lytic virus. A likely scenario is that T cells prevent
reactivation of latently infected cells, and Ab prevents the
dissemination of reactivating lytic virus. A similar role for Abs has
been previously described for murine CMV, a 
-herpesvirus
(35). Ab-mediated protection is presumably mediated by
direct neutralization, although the current studies do not specifically
address the mechanism.
Although both Ab and T cells contributed to the control of recrudescent lytic virus, differences in viral latency were noted in the absence of T cells, whether or not Abs were present. This was indicated by the increased ability of latently infected spleen cells in T cell-depleted mice to reactivate in vitro. In the normal course of infection, latently infected spleen cells reactivate readily in vitro early after the establishment of MHV-68 latency (within 2–3 wk), but long-term latency is not detectable by in vitro reactivation, although the frequency of latently infected cells drops only slightly (6, 19), suggesting alternative states of latency. The transition is thought to be controlled by CD8+ T cells, which either drive latently infected cells to an altered form of latency, or selectively eliminate cells capable of in vitro reactivation (33). Thus, there are two possible explanations for the increase in in vitro reactivation from latency in the absence of T cell immunosurveillance observed in the current studies. One possibility is that T cell depletion allows a qualitative change in latency: a "reversion" of pre-existing latently infected cells to a less restricted form of latency more prone to in vitro reactivation. A second possibility is that recent reinfection by recrudescent lytic virus contributes to the increase in the number of latently infected cells capable of in vitro reactivation. The observation that there is an increase in latently infected cells capable of in vitro reactivation in B6 mice with intact humoral immunity that would prevent reinfection supports the first possibility. The higher and more consistent levels of reactivation seen in the CD28-/- mice that lack neutralizing Abs, compared with control mice with intact humoral immunity, is consistent with the second possibility.
B cell-deficient µMT mice have been widely used to study immunity in
the absence of Abs. However, because B cells are an important reservoir
of -herpesvirus latency and play an essential role in the
dissemination of latent virus (11, 12, 14, 19), µMT mice
are not suitable for analyzing the immune control of -herpesvirus
latency because they do not develop normal reservoirs of latency
(11, 39). An important aspect of the current study is that
not only was recrudescent lytic virus detectable in the lung as had
previously been shown after T cell-depletion of µMT mice
(11), but recrudescent lytic virus was also detected in
the spleens of T cell-depleted CD28-/- mice.
Presumably virus had reactivated from latently infected epithelial
cells in the lungs of µMT mice, whereas reactivation in the spleen in
the CD28-/- mice was from B cells, as well as
other latently infected cell types. The data suggest that there may be
cell type- or tissue-specific T cell immune control of persistent
virus, as both CD4+ and
CD8+ T cells were required to prevent
recrudescence in the lung, whereas either CD4+ or
CD8+ T cells were sufficient to control
reactivation of lytic virus in the spleen. These data reinforce the
premise that immune control of persistent -herpesviruses is
optimally studied in models with normal B cell latency.
The generation of a class-switched virus-specific response in the
absence of germinal centers in CD28-/- mice is
not entirely unexpected. It has been shown that although germinal
centers are a site of isotype switching, they are not essential, as
isotype switching occurs largely in the periarteriolar lymphoid sheaths
(40). Affinity maturation has also been shown to occur in
the absence of germinal centers (41). The Ab response
after viral infection has also been analyzed in other mouse strains
deficient in germinal center formation. For example, lymphotoxin
-/- mice showed isotype-switched Abs at day
50 after MHV-68 infection, although the virus neutralizing activity was
not assessed (42). In TNFR-/-
mice, initially vesicular stomatitis virus-specific Ab induced by live
virus was of comparable neutralizing titer to controls, but waned with
time (43). In the current studies, the poor neutralizing
and waning Ab response is likely independent of the absence of germinal
centers per se, but is a consequence of impaired
CD4+ T cell help. Although Ab responses against
proteins normally require T cell help, it has been shown that viral
infections can elicit strong T-independent protective Ab responses
(44). Consistent with the data shown here for MHV-68
humoral immunity in CD28-/- mice, T-independent
anti-viral responses typically have a short half-life and are
non-neutralizing.
It has been shown that EBV latency in the peripheral blood is harbored in resting memory B cells, and it has been suggested that the virus exploits the normal germinal center reaction to gain access to the memory B cell compartment, as a mechanism for maintaining a long-term reservoir of latency in immunocompetent individuals (45). Our data show that germinal center reactions are not essential for maintaining the reservoir of B cells latently infected with MHV-68, as B cell latency is maintained at normal levels in CD28-/- mice, which are deficient in germinal center reactions. The current data also rule out the possibility that the virus overcomes the requirement for CD28 in germinal center reactions, as we previously suggested (14). However, it has been shown that memory B cells can be generated and maintained in the absence of germinal center reactions (43), so further studies will be required to address whether viral latency in memory B cells is a strategy used by the virus to facilitate the maintenance of long-term latency without the necessity for viral reactivation.
Finally, these studies showing the importance of Abs in controlling the
persistent stage of MHV-68 infection are consistent with limited data
showing a contribution of anti-viral Abs to immune control of
persistent EBV, and have important implications for clinical
intervention to prevent -herpesvirus reactivation in
immunosuppressed patients. An association has been noted between
anti-EBV Abs, specifically against EBV-encoded nuclear Ag-1,
and posttransplant lymphoproliferative disease (46, 47).
In addition, experimental evidence suggested that Ab transfer reduced
the risk of development of EBV-associated lymphoma in SCID mice
(48, 49). Based on the correlation in humans and the
experimental data in SCID mice, high-dose i.v. gamma globulin,
containing high levels of anti-EBV Abs, has been incorporated into
some combined treatment protocols for posttransplant
lymphoproliferative disorders following solid organ transplant
(48, 50). However, Ig therapy is not widely used in the
prevention and treatment of posttransplant lymphoproliferative
syndromes, and only recently have clinical trials been initiated to
establish the efficacy of anti-viral Ab therapy (48).
Adoptive T cell immunotherapy has been successful in the prevention of
EBV posttransplant lymphoproliferative disease in bone marrow
transplants (3), in which the proliferating B cells are
usually of donor origin. In solid organ recipients, the proliferating B
cells are usually derived from the recipient (51). Thus,
Ab-mediated therapy is especially attractive for preventing primary
infection or transmission of virus from donor to recipient in
EBV-negative transplant recipients. In addition, passive transfer of
Abs may provide transient protection during periods of therapeutic
immunosuppression.
In conclusion, we have definitively shown that, in the absence of both
CD4+ and CD8+ T cells, Ab
is sufficient for immune control of a -herpesvirus. These data
emphasize the importance of clinical studies to address the ability of
high-titered Ig to control -herpesvirus infection in
immunocompromised individuals, and support the idea of an EBV vaccine
for transplant candidates who lack circulating EBV-specific Abs
(48).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marcia A. Blackman, Trudeau Institute, 100 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: mblackman{at}trudeauinstitute.org
3 Abbreviations used in this paper: MHV-68, murine -herpesvirus-68; PNA, peanut agglutinin; ORF, open reading frame.
Received for publication December 19, 2001. Accepted for publication February 6, 2002.
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References |
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 B. Kayhan, E. J. Yager, K. Lanzer, T. Cookenham, Q. Jia, T.-T. Wu, D. L. Woodland, R. Sun, and M. A. Blackman A Replication-Deficient Murine {gamma}-Herpesvirus Blocked in Late Viral Gene Expression Can Establish Latency and Elicit Protective Cellular Immunity J. Immunol., December 15, 2007; 179(12): 8392 - 8402. [Abstract] [Full Text] [PDF]
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S. S. Cush, K. M. Anderson, D. H. Ravneberg, J. L. Weslow-Schmidt, and E. Flano Memory Generation and Maintenance of CD8+ T Cell Function during Viral Persistence J. Immunol., July 1, 2007; 179(1): 141 - 153. [Abstract] [Full Text] [PDF]
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S. Fuse, S. Bellfy, H. Yagita, and E. J. Usherwood CD8+ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand J. Immunol., April 15, 2007; 178(8): 5227 - 5236. [Abstract] [Full Text] [PDF]
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I.-J. Kim, C. E. Burkum, T. Cookenham, P. L. Schwartzberg, D. L. Woodland, and M. A. Blackman Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs J. Immunol., February 1, 2007; 178(3): 1692 - 1701. [Abstract] [Full Text] [PDF]
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S. Fuse, J. J. Obar, S. Bellfy, E. K. Leung, W. Zhang, and E. J. Usherwood CD80 and CD86 Control Antiviral CD8+ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68. J. Virol., September 1, 2006; 80(18): 9159 - 9170. [Abstract] [Full Text] [PDF]
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V. L. Tarakanova, F. Suarez, S. A. Tibbetts, M. A. Jacoby, K. E. Weck, J. L. Hess, S. H. Speck, and H. W. Virgin IV Murine Gammaherpesvirus 68 Infection Is Associated with Lymphoproliferative Disease and Lymphoma in BALB {beta}2 Microglobulin-Deficient Mice J. Virol., December 1, 2005; 79(23): 14668 - 14679. [Abstract] [Full Text] [PDF]
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E. S. Barton, M. L. Lutzke, R. Rochford, and H. W. Virgin IV Alpha/Beta Interferons Regulate Murine Gammaherpesvirus Latent Gene Expression and Reactivation from Latency J. Virol., November 15, 2005; 79(22): 14149 - 14160. [Abstract] [Full Text] [PDF]
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B. J. Lee, F. Giannoni, A. Lyon, S. Yada, B. Lu, C. Gerard, and S. R. Sarawar Role of CXCR3 in the Immune Response to Murine Gammaherpesvirus 68 J. Virol., July 15, 2005; 79(14): 9351 - 9355. [Abstract] [Full Text] [PDF]
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F. Giannoni, A. B. Lyon, M. D. Wareing, P. B. Dias, and S. R. Sarawar Protein Kinase C {theta} Is Not Essential for T-Cell-Mediated Clearance of Murine Gammaherpesvirus 68 J. Virol., June 1, 2005; 79(11): 6808 - 6813. [Abstract] [Full Text] [PDF]
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D. C. Braaten, R. L. Sparks-Thissen, S. Kreher, S. H. Speck, and H. W. Virgin IV An Optimized CD8+ T-Cell Response Controls Productive and Latent Gammaherpesvirus Infection J. Virol., February 15, 2005; 79(4): 2573 - 2583. [Abstract] [Full Text] [PDF]
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