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J Virol, August 1998, p. 6559-6564, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Critical Role for CD4+ T Cells in
Controlling Retrovirus Replication and Spread in Persistently
Infected Mice
Kim J.
Hasenkrug,*
Diane M.
Brooks, and
Ulf
Dittmer
Laboratory of Persistent Viral Diseases,
Rocky Mountain Laboratories, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Hamilton,
Montana 59840
Received 9 January 1998/Accepted 13 May 1998
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ABSTRACT |
Reactivations of persistent viral infections pose a significant
medical problem in immunocompromised cancer, transplant, and AIDS
patients, yet little is known about how persistent viral infections are
immunologically controlled. Here we describe a mouse model for
investigating the role of the immune response in controlling a
persistent retroviral infection. We demonstrate that, following
recovery from acute Friend virus infection, a small number of B cells
evade immunological destruction and harbor persistent virus. In vivo
depletions of T-cell subsets in persistently infected mice revealed a
critical role for CD4+ T cells in controlling virus
replication, spread to the erythroid lineage, and induction of
erythroleukemia. The CD4+ T-cell effect was independent of
CD8+ T cells and in some cases was also independent of
virus-neutralizing antibody responses. Thus, the CD4+ T
cells may have had a direct antiviral effect. These results may have
relevance for human immunodeficiency virus (HIV) infections where loss
of CD4+ T cells is associated with an increase in HIV
replication, reactivation of persistent viruses, and a high incidence
of virus-associated cancers.
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INTRODUCTION |
A wide range of viruses not only
induce acute diseases in humans but also employ various methods to
evade immunological destruction and establish persistent infections.
These include hepatitis B virus, adenoviruses, rubella virus, measles
virus, JC and BK polyomaviruses, several herpesviruses, human
T-lymphotropic viruses, and human immunodeficiency virus (HIV). In most
cases, persistent viral infections are innocuous and cause few serious
clinical problems (14). However, if the host becomes
immunocompromised due to drug therapies or infection with an
immunosuppressive virus such as HIV, persistent viruses can reactivate
and cause lethal diseases. For example, cytomegalovirus infections are
a leading cause of mortality in AIDS patients and transplant patients,
and a large proportion of the infections are due to reactivated viruses
(15, 18, 22, 32). In addition, increased rates of cancer are also observed in immunocompromised patients, especially cancers associated with virus infections, such as non-Hodgkin's lymphoma, Kaposi's sarcoma, and adult T-cell leukemia (14). Although
it is widely accepted that the cause of persistent virus reactivations is immunosuppression, the specific types of immune cells which normally
control persistent viruses have not been identified.
In order to investigate this issue in vivo, we utilized mice
persistently infected with Friend virus complex (FV). FV is an oncogenic complex of two retroviruses, a replication-competent virus
known as Friend murine leukemia helper virus (F-MuLV) and a
replication-defective component called spleen focus-forming virus
(SFFV). Coinfection of cells by the two viruses allows SFFV to be
packaged into particles formed from helper virus proteins. Infection of
susceptible mice with FV induces an SFFV-dependent, polyclonal
proliferation of erythroid precursors in the spleen, which leads to
erythroleukemia unless the infection is controlled by immune responses
(1, 13, 16). Mice of the strain chosen for these experiments
mount potent immune responses and are able to recover from acute
disease. Virus-specific T-helper, cytotoxic T-lymphocyte
(CTL), and antibody responses are all required for such recovery
(4, 12, 30). Although 95% of recovered mice show no
clinical signs and have a normal life span, it has been shown
previously that the animals remain persistently infected with low
levels of virus in the spleen (3). Despite the inability of
the immune system to totally eradicate FV infections, experiments have
suggested that persistent FV is nevertheless under immune control. For
example, it has been shown previously that spleen cell transfers from
persistently infected mice to naive mice induce rapid acute disease
(5), indicating that a host immune mechanism rather than
virus mutation might be responsible for keeping persistent virus in
check.
In this report, we show that the primary reservoir for persistent FV
infection in the spleen is a small subset of B cells. In at least half
of the mice, replication of virus and spread to other cell types are
shown to be controlled by a subpopulation of T cells.
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MATERIALS AND METHODS |
Mice.
The mice used in this study were age- and sex-matched
(C57BL/10 × A.BY)F1 mice of 3 to 6 months of age at
experimental onset. Parental strains were obtained from Jackson
Laboratories, and breeding of F1 strains was done at Rocky
Mountain Laboratories. All animals were treated in accordance with the
regulations of the National Institutes of Health and the Animal Care
and Use Committee of Rocky Mountain Laboratories. Relevant Friend virus resistance genotypes in (C57BL/10 × A.BY)F1 mice are
H-2b/b, Fv-1b/b,
Fv-2r/s, and Rfv-3r/s.
Virus and virus infections.
The FV used in these experiments
was a stock obtained from a 10% spleen cell homogenate from BALB/c
mice infected 9 days previously. It is an FV-1 B-tropic,
polycythemia-inducing strain originally obtained from Frank Lilly. Mice
were injected intravenously with 0.5 ml of phosphate-buffered, balanced
salt solution containing 2% fetal bovine serum and 1,500 spleen
focus-forming U of FV.
Splenomegaly as a measure of Friend disease.
Palpation for
splenomegaly is the standard procedure used to monitor the progression
of Friend disease (8, 11, 28) and was used in the following
manner: at weekly intervals, individual animals under general
anesthesia were palpated in a blinded fashion and rated on a scale of
1+ to 4+. Spleens rated 1+ were
palpated as less than twice normal size and weighed less than 0.4 g. Normal spleen weights ranged from 0.1 to 0.25 g. Spleens rated
2+ were palpated as more than twice normal size but not
large enough to reach the ventral midline and weighed between 0.4 and
0.8 g. Spleens rated 3+ were large enough to reach the
ventral midline and weighed between 0.8 and 1.6 g. Spleens rated
4+ were severely enlarged to more than 1.6 g, extended
across the abdominal midline, and caused protrusion of the abdominal
wall. Cross-checking of actual spleen weights against spleen sizes
determined by palpations has shown that spleens weighing more than
0.4 g (2+) can accurately be differentiated from
spleens in the normal weight range of 0.1 to 0.25 g (3,
12a). It should be noted that mice with sustained FV-induced
splenomegaly for longer than 6 weeks generally have 3+ or
4+ spleens and that there is no ambiguity regarding their
clinical status. Such mice display additional hallmarks of
erythroleukemia such as hematocrits greater than 85% and high numbers
of erythroid precursors in the blood. However, monitoring these
attributes requires bleeding of the mice, which exacerbates Friend
disease by stimulating erythropoiesis and is less accurate than spleen palpation at predicting clinical outcome.
T-cell depletions.
T-cell depletions were performed
essentially as described elsewhere (6, 12, 25). Briefly,
persistently infected mice were inoculated intraperitoneally with 0.5 ml of supernatant fluid obtained from tissue culture for monoclonal
antibody (MAb) 169.4 (anti-CD8) or from artificial capillary cultures
(Cellco, Germantown, Md.) for 191.1 (anti-CD4). Mice were inoculated
three times per week for 2 weeks. The MAbs were both of the rat
anti-mouse immunoglobulin G2b isotype. Blood samples from all mice were
checked for T-cell depletion levels by flow cytometry at 7 to 10 days
following the last injection of antibody. T-cell subset levels in
mononuclear blood cells from depleted mice ranged from <1 to 3% of
the nucleated peripheral blood cells, and levels of depletion did not
correlate with relapse (data not shown).
Infectious center assays on specific cell lineages.
Single-cell suspensions from persistently infected mouse spleens
were sorted with a FACStar flow cytometer (Becton Dickinson Immunocytometry Systems, San Jose, Calif.) modified for five-parameter analysis. The following tissue-specific MAbs were used for
sorting and analyses: anti-Ter 119 (erythroid lineage)
(17), anti-Mac-1 (M1/70.15.11.5.HL) (33),
anti-CD4 (clone GK1.5) (9), anti-CD8 (169.4) (6),
anti-B220 (RA3-6B2) (7), and anti-CD19 (19). Fluorescently labeled antibodies were obtained from Pharmingen, San
Diego, Calif. In the first experiment reported in Table 1, T cells for
the infectious center assay were enriched with T-cell subset enrichment
columns (R&D Systems, Minneapolis, Minn.). Sorted and enriched
populations were plated onto Mus dunni cells
(20), cocultivated for 5 days, fixed with ethanol, and
stained with F-MuLV envelope-specific MAb 720 (29), followed
by goat anti-mouse antibody peroxidase conjugate (Cappel, West Chester,
Pa.) and development with 3-amino-9-ethylcarbazole (AEC) substrate to
detect foci.
Viremia and virus-neutralizing antibody assays.
For viremia
assays, freshly frozen plasma samples were titrated on susceptible
M. dunni cells as described above for detection of spleen
foci, except that the cells were pretreated with 4 µg of Polybrene
per ml. To test plasma samples for virus-neutralizing antibodies,
heat-inactivated (56°C, 10 min) samples at titrated dilutions were
incubated with virus stock in the presence of complement at 37°C as
previously described (23). Samples were then plated as
described for the viremia assay for detection of foci.
Cytokine analyses.
Cytokine gene transcription was measured
by an RNase protection assay with the RiboQuant system (Pharmingen).
Assays were performed with 1 µg of mRNA isolated from
CD4+ T cells from uninfected and persistently infected
(C57BL/10 × A.BY)F1 mice. Spleens from six mice of
each group were pooled, and >90% pure CD4+ T cells were
obtained with T-cell subset enrichment columns (R&D Systems).
Quantifications were done by phosphorimaging analyses.
CD4+ T-cell surface marker analyses.
Nucleated
spleen cell suspensions were made from six uninfected mice and eight
persistently infected mice. The cells were analyzed by flow cytometry
with a FACStar flow cytometer modified for five-parameter analysis.
CD4+ gated cells (104) were analyzed for
expression of the CD69 activation marker (34) and the CD45RB
memory marker (10). Labeled antibodies were obtained from
Pharmingen. The data were analyzed by the Mann-Whitney test for
statistical significance.
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RESULTS |
B cells are the primary reservoir of persistent F-MuLV.
The
number of spleen cells infected with F-MuLV in persistently infected
animals has been reported to range between 0.003 and 0.3%
(3), but the types of cells involved in persistence have not
been determined. For the current studies, it was important to establish
the identity of these cells so that virus spread to other lineages
following immunosuppression could be assessed. To address this issue,
spleen cell suspensions from persistently infected mice were enriched
for the major cell lineages. The enriched populations were then plated
as infectious centers onto virus-susceptible indicator cells to produce
foci. The first experiment revealed that B220+ cells
accounted for the vast majority of the infectious centers (Table
1). Based on this finding, two subsequent
experiments in which spleen cells from persistently infected mice were
sorted on the basis of B220 expression were performed. In both cases, the B220-positive subpopulation contained almost all of the infectious centers (Table 1). When both the B220-positive and the B220-negative subpopulations were resorted to 99% purity before plating, 97% of the
total infectivity was contained in the B220-positive population (Table
1). Since the B220 antigen (CD45R) is expressed on small populations of
cells other than B cells, we also did similar studies with
CD19+ cells. CD19 is reported elsewhere to be B cell
specific (19), and in three persistently infected mice, we
found more than 90% of the infectivity in the CD19+
fraction (data not shown). Thus, B cells were the major reservoir for
persistent F-MuLV in the spleens of these mice.
These results contrasted with data obtained from mice at 1 week
postinfection. In addition to B cells, cells of the erythroid
and
monocytic/granulocytic lineages were also heavily infected
during acute
infection (Table
1). Very little or no infection
was associated with T
cells in either acute or persistent infection.
Furthermore, acutely
infected mice had in the range of 1,000 times
more infectious centers
per spleen than persistently infected
mice, and although large numbers
of B cells were infected early,
they did not make up the bulk of the
infection (Fig.
1).
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FIG. 1.
Infectious centers from spleens of persistently infected
and acutely infected mice. Nucleated spleen cell suspensions were
sorted by flow cytometry on the basis of B220 expression and plated as
infectious centers as described for Table 1. The numbers of infectious
centers per spleen were extrapolated from data from approximately
3 × 106 B cells and 6 × 106 total
cells per mouse. These data are derived from the same mice analyzed for
Table 1.
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Induction of splenomegaly, virus spread, and erythroleukemia by CD4
depletion but not by CD8 depletion.
To determine whether host
T-cell responses were responsible for keeping persistent virus in
check, persistently infected mice were injected with specific MAbs to
deplete T-cell subsets. The in vivo effectiveness of the CD8 depletion
protocol was tested as described in the legend to Fig.
2. Only 1 of 19 animals depleted of
CD8+ T cells became splenomegalic. This result was not
statistically different from that for the nondepleted control group,
and it is unknown whether the relapse was spontaneous or was induced by
CD8 depletion. Two to five percent of untreated, persistently infected
mice can be expected to relapse sometime during their life spans
(5). The reasons for spontaneous relapses are unknown.
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FIG. 2.
Splenomegaly in T-cell-depleted mice. Persistent FV
infections were established and depletions were performed as described
in Materials and Methods. Numbers of mice in the groups were as
follows: CD4-depleted group, n = 27; CD8-depleted
group, n = 19; nondepleted group, n = 34. The data were analyzed by Fisher's exact test of contingency
tables. There was a significant difference between the CD4-depleted
group and the nondepleted group (P = 0.0049). The
difference between CD4 depletion and CD8 depletion was also significant
(P = 0.0027). There was no significant difference
between CD8 depletion and no depletion (P = 0.3585).
The efficacy of CD8 depletion was tested in a side-by-side control
group of mice with acute FV infection. We have previously shown that
acutely infected, CD8-depleted mice have poor recovery and develop
erythroleukemia at a high rate (79%) (30). Six of eight
CD8-depleted control mice developed erythroleukemia (75%) compared to
0 of 16 nondepleted mice. Dual depletion of both CD4 and CD8 did not
increase relapse above the level with CD4 depletion alone (data not
shown).
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In contrast to the CD8 depletions, animals depleted of CD4
+
T cells showed a marked increase in disease. Beginning at 2 weeks
after
the initiation of CD4 depletions, mice began to show grossly
enlarged
spleens indicative of FV-induced erythroproliferation
(Fig.
2). The
percentage of affected mice increased over the next
month to
approximately one-half of the treated group. No spontaneous
relapses of
splenomegaly were observed in the control group during
this time.
Flow cytometric analysis of an enlarged spleen from a CD4-depleted
mouse revealed typical FV-induced erythroproliferation
with more than
90% of the spleen cells expressing the Ter 119
erythroid lineage
marker (Fig.
3). This was in sharp
contrast
to the profile for a typical nondepleted mouse, which showed
less
than 13% Ter 119
+ cells. In addition, the Ter
119
+ population from the CD4-depleted mouse showed a very
abnormal
size distribution with high percentages of both very small and
very large cells. Infectious center assays of a CD4-depleted enlarged
spleen revealed that the Ter 119
+ cells accounted for 74%
of the infectious centers in the spleen,
indicating that there was
massive infection as well as proliferation
of erythroid cells (data not
shown).
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FIG. 3.
Flow cytometric analysis of nucleated spleen cells.
Single-cell suspensions from spleens were labeled with biotin-Ter 119, stained with fluorescein isothiocyanate-avidin, and analyzed as
described in Materials and Methods. Results are presented as contour
plots generated with Consort 30 software. (A) Cells from a nondepleted,
persistently infected mouse with no palpable splenomegaly. Ter
119-positive cells were 12.4% of the total. (B) Cells from a
CD4-depleted, persistently infected mouse with gross splenomegaly. Ter
119-positive cells were 91.5% of the total.
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One group of nine CD4-depleted mice which had four mice with
splenomegaly was monitored over the long term. At 7 weeks
postdepletion,
one mouse recovered, possibly due to repopulation of its
T-cell
compartment. The other three mice developed fatal
erythroleukemias.
Thus, the disease induced by depletion of
CD4
+ T cells progressed from erythroproliferation to
leukemia in most
cases.
Increased virus replication in CD4-depleted, relapsed mice.
Infectious center assays were done to determine how T-cell depletions
affected levels of virus replication in the spleen. Consistent with
previous findings, the persistently infected, nondepleted mice had
levels of infection that ranged between 0.001 and 0.2% of spleen cells
(5). In contrast, CD4-depleted mice that developed palpable
splenomegaly had mean infectious center titers more than 1,000-fold
higher than titers from the other groups (Fig.
4).
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FIG. 4.
Infectious center assays of virus-producing cells in the
spleens of persistently infected mice. Spleen cell suspensions were
plated onto indicator cells to produce infectious centers as described
in Materials and Methods. Nonrelapsed mice are indicated by open
circles, and relapsed splenomegalic mice are indicated by closed
circles. There were significantly more infectious centers in
CD4-depleted relapsed mice (mean = 3.4 × 107)
than in the CD4-depleted nonleukemic group (mean = 1.9 × 104; two-tailed P < 0.0001 by Mann-Whitney
test). The numbers of infectious centers in the CD4-depleted,
nonleukemic group were not significantly different from those for the
control group or the CD8-depleted group.
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In addition to spleen infectious centers, CD4-depleted mice were also
assayed for the presence of plasma viremia and virus-neutralizing
antibodies. Previous studies with acutely infected mice have
demonstrated
that plasma viremia is controlled by virus-neutralizing
antibodies
(
2,
4). Two-thirds of the CD4-depleted, relapsed
mice had
high titers of virus in their blood, while none of the
nonrelapsed
mice had detectable virus (Table
2). Virus-neutralizing antibody
titers
were reduced in the viremic mice, likely due to absorption
of
antibodies by free virus. Two mice relapsed with splenomegaly
while
maintaining virus-neutralizing antibodies which were still
controlling
viremia. These mice may have been at an earlier stage
of disease at
which virus replication had not yet outpaced antibody
production.
Induction of splenomegaly in the presence of virus-neutralizing
antibodies indicated that antibody loss was not the reason for
relapse
in these two CD4-depleted mice.
In summary, depletion of CD4
+ T cells in many cases allowed
increased FV replication, permitted spread of virus from
persistently
infected B cells to the erythroid compartment, and
significantly
increased relapses of splenomegaly due to
erythroproliferation.
In most cases studied, virus spread to the
blood and erythroproliferative
disease progressed to
erythroleukemia.
Differences in CD4+ T cells from persistently infected
mice and those from uninfected mice.
The mechanism of
CD4+ T-cell-mediated control of persistent virus was
investigated by analyzing cytokine mRNA levels by an RNase protection
assay. Comparisons of mRNAs isolated from splenic CD4+ T
cells showed no significant differences between uninfected and
persistently infected mice (Fig. 5).
Given that the virus-specific CD4+ T cells were likely a
small percentage of the total splenic CD4+ T cells,
this assay may not have been sensitive enough to detect a
difference. Alternatively, the effector(s) could have been a cytokine or a factor not included in the assay.
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FIG. 5.
Cytokine analyses. Levels of cytokine transcripts from
purified CD4+ T cells derived from normal mice (solid bars)
and persistently infected mice (open bars) were compared by RNase
protection assays. The cells were not restimulated in vitro. Band
densities are expressed as ratios of specific cytokine band density to
the density of an internal housekeeping transcript band
(glyceraldehyde-3-phosphate dehydrogenase [GAPDH]). Additional
cytokine transcripts which were analyzed but did not give detectable
bands were those of interleukin 9, interleukin 13, interleukin 15, transforming growth factor  2, and gamma interferon. Abbreviations:
IL, interleukin; TNF, tumor necrosis factor; TGF, transforming growth
factor; LT, lymphotoxin; IFN, interferon.
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Flow cytometric analyses were also performed to determine if surface
expression of memory or activation markers could be used
to distinguish
CD4
+ T-cell subpopulations obtained from persistently
infected mice
from those obtained from uninfected mice. No
significant differences
were found in expression of the CD45RB
memory marker (data not
shown). However, persistently infected mice had
a 4% increase
in the number of splenic CD4
+ T
cells expressing the CD69 activation marker (Table
3). This
increase in activated
CD4
+ T cells from persistently infected mice was
statistically significant
and may reflect the percentage of
CD4
+ T cells involved in virus control at a given time.
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TABLE 3.
Expression of the CD69 activation marker on
CD4+ T cells from spleens of uninfected and
persistently FV-infected mice
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DISCUSSION |
(C57BL/10 × A.BY)F1 mice acutely infected with
FV develop complex immune responses including CD4+ T helper
cells, CD8+ CTLs, and virus-neutralizing antibodies, which
collectively are able to clear infection from almost every cell,
including most infected B cells. However, we found a very small
subpopulation of B cells acting as a reservoir for persistent FV. We
estimate that the number of B cells infected with FV ranges between 100 and 1,000 cells per spleen. The narrowing of FV infection to B cells
during resolution of acute infection suggests an immunological escape
mechanism specific to that cell type. It is unlikely that B cells are
the major reservoir of persistent virus simply by chance because,
within an order of magnitude, Mac-1+ cells account for as
much infectivity during acute infection as do B220+ cells
(Table 1), yet Mac-1+ cells were not observed to carry
persistent virus. It is more likely that there is a unique
microenvironment which is specific to a subset of B cells or which is
induced by the virus in only a small fraction of infected B cells. Due
to the very low percentage of B cells which are persistently infected,
and because we have not observed surface expression of FV antigens on B
cells from persistently infected mice, we have not yet been able to
investigate some of the interesting questions about these cells.
Viruses have been reported elsewhere to employ a wide variety of
methods to escape killing by CTLs (reviewed in reference 27), the main immunological effectors responsible
for specifically eliminating virus-infected cells. Since the very
presence of persistent virus indicates escape from CTL destruction, it
was not totally unexpected that we found no significant role for
CD8+ T cells in controlling persistent FV disease. For the
lymphocytic choriomeningitis virus model of persistent viruses, CTL
exhaustion, in which all reactive CTLs are induced during acute
infection and subsequently disappear, has been described
(24). This mechanism of immunological escape does not appear
to be operating in persistent FV infections because rechallenge of
persistently infected mice with FV induces strong CTL responses at 1 week postchallenge (data not shown). Thus, the animals still possess
FV-specific CTLs, but those CTLs are ineffective at eliminating
persistent virus from B cells.
In contrast to the lack of effect from CD8+ T cells, we
were able to establish, for the first time, a critical in vivo role for
CD4+ T cells in controlling persistent FV infections in
many mice. It is known in the lymphocytic choriomeningitis virus model
that CD4+ T cells are necessary for the maintenance of
CD8+ CTL responses during chronic infections
(21). However, in the FV model that we describe, CD8
depletions did not induce relapses, nor did dual depletions of both
CD4+ and CD8+ cells have an additive effect
(data not shown). Thus, the mechanism of CD4+
T-cell-mediated control appeared to be independent of CD8+
T cells. Two mice which maintained good titers of virus-neutralizing antibodies and controlled blood viremia, even after CD4 depletion and
relapse of splenomegaly, were found. Thus, at least in some cases, a
CD4+ T-cell function other than immunological help for CTLs
or B cells may have been responsible for controlling virus replication
and spread in the spleen. For most mice, it appeared that virus
production rapidly swamped production of virus-neutralizing antibodies
and that the animals became viremic as well as splenomegalic.
One of the most interesting questions raised by these studies is how
CD4+ T cells control retrovirus replication and spread.
While the current studies do not answer this question, the findings
point to an antigen-specific interaction because the CD69 early
activation marker is upregulated only in the presence of cognate
antigen presented by major histocompatibility complex (MHC) class II
molecules (34). B cells are one of the few types of cells
which express MHC class II molecules and thus could serve as targets
for recognition by CD4+ T cells. Clearly, these studies
raise interesting questions regarding presentation of endogenous
antigens by MHC class II molecule cells as well as questions regarding
CD4+ T-cell control of persistent retroviruses.
In each T-cell depletion experiment that was performed, we observed
induction of splenomegaly in only about half of the animals. Although
antibody-mediated T-cell depletions are quite effective in reducing
T-cell populations, residual CD4+ T cells could potentially
have an immunological effect. This is especially true in the spleen,
where it is more difficult than in the periphery to deplete T cells
with antibody. Use of CD4+ T-cell knockout mice is not
possible because such mice cannot recover from acute FV infection.
Alternatively, the data may suggest that factors other than
CD4+ T cells may help keep persistent virus in check.
Another possibility is that the viral load of the animal may affect
whether they relapse. It is evident from Fig. 4 that some animals have
levels of persistent virus 10 to 100 times higher than those of other,
identically treated mice. This extent of variability could impact the
severity of the response to CD4 depletion, and it was not possible to
assess the extent of persistent infection prior to treatment. Finally, it is possible that persistent infection in some of the mice consisted primarily of helper virus rather than the complex of both helper (F-MuLV) and SFFV. The assay we used detects only persistent F-MuLV, a
necessary component for pathogenesis. It was previously shown that
levels of persistent helper virus are 30-fold higher than levels of
persistent complex (5). Since only complex is pathogenic in
adult animals, animals with low levels of helper virus and even lower
levels of cells infected by complex might not relapse.
The findings presented here have implications for vaccination against
viruses able to establish persistent infections. We found massive
infection of B cells as early as 1 week postinfection, indicating that
persistence might be established quite early as well. Therefore,
prevention of persistent FV would require either complete protection
from infection or severe limitation of infection combined with rapid
destruction of infected B cells. Little is known about the prevention
of persistent infections, and it is doubtful whether immune responses
can completely prevent infection. However, in lymphocytic
choriomeningitis virus of mice, a vaccine which primes the CTL
response has been shown to prevent persistent infection through rapid
destruction of infected cells (26). Previous vaccine studies
with Friend virus have demonstrated protection from acute disease but
no protection from persistent infection, even though the vaccines
primed CTL responses (11). Thus, protection from retroviral
persistence may be more difficult to obtain than protection from
viruses which do not integrate into the genome. Consideration of
retroviral persistence may be a crucial aspect of vaccine development,
especially for viruses such as HIV, which are immunosuppressive and
have the potential to reactivate themselves by damaging the
host's resistance mechanisms. Recent studies show a critical role
for CD4+ T cells in controlling HIV viremia
(31). The FV model that we describe here provides the
opportunity to study the basic mechanisms for both prevention and
control of persistent retroviral infections.
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FOOTNOTES |
*
Corresponding author. Mailing address: Laboratory of
Persistent Viral Diseases, Rocky Mountain Laboratories, National
Institute of Allergy and Infectious Diseases, National Institutes of
Health, 903 S. 4th St., Hamilton, MT 59840. Phone: (406) 363-9310. Fax: (406) 363-9204. E-mail: KHasenkrug{at}nih.gov.
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Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
