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Journal of Virology, October 2000, p. 9594-9600, Vol. 74, No. 20
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Cytopathicity of Human Immunodeficiency Virus Type 2 (HIV-2)
in Human Lymphoid Tissue Is Coreceptor Dependent and Comparable to
That of HIV-1
Birgit
Schramm,1
Michael L.
Penn,1,2
Emil
H.
Palacios,1
Robert M.
Grant,1,2,3
Frank
Kirchhoff,4 and
Mark A.
Goldsmith1,2,3,*
Gladstone Institute of Virology and
Immunology,1 Department of
Medicine,3 and School of
Medicine,2 University of California San
Francisco, San Francisco, California 94141-91000, and Institute
for Clinical and Molecular Virology, University of
Erlangen-Nürnberg, 91054 Erlangen,
Germany4
Received 6 April 2000/Accepted 28 July 2000
 |
ABSTRACT |
Epidemiological studies have shown that human immunodeficiency
virus type 2 (HIV-2) is markedly less pathogenic than HIV-1 in vivo.
Individuals infected with HIV-2 exhibit a remarkably slow rate of
disease development, and these clinical properties have been attributed
presumptively to an "attenuated" phenotype of HIV-2 itself. Here,
we investigated the impact of coreceptor usage on the cytopathicity of
HIV-2 and compared its pathogenic potential with that of HIV-1 in a
unique human lymphoid histoculture model. We found that HIV-2 strains,
as well as closely related simian immunodeficiency viruses (SIV),
displayed mildly or highly aggressive cytopathic phenotypes depending
on their abilities to use the coreceptor CCR5 or CXCR4, respectively. A
side-by-side comparison of primary X4 HIV-1 and HIV-2 strains revealed
similar, high degrees of cytopathicity induced by both HIV types.
Furthermore, we found that HIV-2 coreceptor specificity for CCR5 and
CXCR4 determined the target cell population for T-cell depletion in lymphoid tissue. Finally, utilization of the alternate coreceptors BOB
and Bonzo did not significantly increase the cytopathic properties of
HIV-2. These findings demonstrate that coreceptor preference is a key
regulator of target cell specificity and the cytopathic potential of
HIV-2, with indistinguishable rules compared with HIV-1. Moreover,
HIV-2 strains are not characterized by an intrinsically lower
cytopathicity than HIV-1 strains. Therefore, direct cytopathic potential per se does not explain the unique behavior of HIV-2 in
people, highlighting that other unknown factors need to be elucidated
as the basis for their lesser virulence in vivo.
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INTRODUCTION |
Human immunodeficiency virus type 2 (HIV-2) is prevalent mainly in West Africa and is found less frequently
in some Asian countries, Western Europe, and the United States. Human
infection with HIV-2 is associated with eventual immunologic failure
and AIDS. However, disease progression has been reported to be much slower in HIV-2-infected individuals compared with HIV-1-infected individuals, as evidenced by significantly slower rates of development of abnormal CD4+ T-cell counts and progression to AIDS
(20, 25, 32, 40). This attenuated virulence of HIV-2
infection in vivo is a compelling area of investigation in which to
elucidate the mechanisms of HIV-induced pathogenesis.
With the discovery of the role of viral coreceptors in cellular entry
by HIV, several studies have revealed that nearly all strains of HIV-2
use CD4 together with the chemokine receptors CCR5 and/or CXCR4
(18, 26-28, 37), the molecules that have been defined as
the major coreceptors for HIV-1 (reviewed in reference 2). In comparison with HIV-1, HIV-2 typically is
more promiscuous in its coreceptor utilization profile (18,
26-28). Specifically, the majority of HIV-2 isolates can use the
orphan receptors BOB and/or Bonzo with efficiencies comparable to their
usage of CCR5 in in vitro assays, a behavior that is similar to that of
the closely related simian immunodeficiency viruses (SIV) (7, 28, 39). The contribution of distinct coreceptor specificities to HIV-2 infection and pathogenesis in vivo nevertheless remains to be
established. In HIV-1 infection, viral coreceptor phenotypes typically
evolve during the course of infection in that CCR5-specific (R5)
viruses predominate in early stages and persist throughout the course
of disease, while CXCR4-using (X4) viruses emerge frequently in
temporal association with rapid CD4+ T-cell decline and
onset of AIDS (10, 33, 35). Several studies have indicated a
similar shift of viral coreceptor specificity for CCR5 and CXCR4 during
the course of HIV-2 infection (27, 28, 37).
We have shown in previous studies that coreceptor specificity
substantially determines the cytopathic potential of HIV-1 and that the
X4 phenotype dramatically enhances HIV-1 virulence in mature lymphoid
tissue ex vivo. These findings indicated that the emergence of X4
viruses in vivo likely accelerates disease progression in
HIV-1-infected individuals due to enhanced cytopathic effects in
peripheral lymphoid tissue (29). We also found that additional coreceptors appear to have little impact on the T-cell depletion potential of HIV-1 strains in lymphoid tissues ex vivo (34). Given the similarities in CCR5 and CXCR4 utilization
patterns and the striking difference regarding the pathogenic potential compared to HIV-1, an important question is how coreceptor preferences relate to the cytopathic potential of HIV-2.
In the present study, therefore, we used an ex vivo human lymphoid
histoculture system to investigate the relationship between coreceptor
preferences and cytopathicity of HIV-2. Histocultures of spleen or
tonsil specimens recapitulate important aspects of HIV pathogenesis in
the tissue microenvironment of major HIV production sites in vivo and
have served in previous studies as a valuable model in which to study
HIV-1 infection (15, 16, 29, 34). A key feature of this
system for studying the impact of HIV coreceptor utilization is that
lymphoid histocultures are readily susceptible to HIV infection without
requiring exogenous stimulation that can alter chemokine receptor
expression patterns (4). Moreover, in this system, the
expression levels of CCR5 and CXCR4 on T lymphocytes remain stable
throughout the culture period. In the present study, we exploited the
lymphoid histoculture system to investigate the impact of coreceptor
preferences on the cytopathicity of HIV-2. Our results demonstrate that
coreceptor specificity markedly influences the cytopathic potential of
HIV-2 and that HIV-2 can be as cytopathic as HIV-1 in mature lymphoid
tissue despite its distinct clinical characteristics.
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MATERIALS AND METHODS |
Viruses and preparation of virus stocks.
The primary HIV-2
isolates A1958 and SLRHC (28) were provided by Beatrice
Hahn, and the HIV-1 primary isolate 12/86 (10) was provided
by Ruth I. Connor. The HIV-2 strain CBL20 (36) was provided
by Robin Weiss, and the primary isolate HIV-2 7924A (14) was
provided by Feng Gao and Beatrice Hahn via the National Institutes of
Health (NIH) AIDS Research and Reference Reagent Program. Virus stocks
of HIV-1 and HIV-2 isolates were established by infection of
heterologous phytohemagglutinin-activated peripheral blood mononuclear
cells (PBMC) that were propagated with interleukin-2 (IL-2) as
described previously (34). Viral stocks of primary SIVsmm
FKl and FBo were established by cocultivation of PBMC derived from two
naturally infected sooty mangabey monkeys from the Yerkes Regional
Primate Research Center with activated mixed heterologous PBMC from
uninfected sooty mangabeys. Donor cells for FBo cultivation were
activated with concanavalin A (5 µg/ml; Sigma) for 48 h. Donor
cells for FK1 cultivation were depleted of CD8 cells (Dynal) and
activated with anti-monkey-CD3 antibody (1 µg/ml; Biosource) for
48 h. Both isolates were cocultured in RPMI medium containing 20%
fetal calf serum and recombinant human IL-2 (100 U/ml; Chiron). The
molecular clone of HIV-2 ST/SXB1 (
JSP4-27) (24) was
provided by Beatrice Hahn, the molecular clone pNL4-3 was provided by
Malcom Martin via the AIDS Research and Reference Reagent Program, and the molecular clone 49-5 (9) was provided by Bruce Chesebro. The molecular clones SIVmac239, SIVmac316, and SIVmac239PS were described previously (22). Infectious virus stocks were
prepared as previously described (6). The p24 and p27 GAG
concentrations of HIV-1, HIV-2, and SIV virus stocks were assessed by
enzyme-linked immunosorbent assay (NEN Life Sciences, Beckman Coulter,
Inc.).
Infection of human lymphoid tissue ex vivo.
Human tonsil and
adenoid tissue removed during routine tonsillectomy (provided by San
Francisco General Hospital, Kaiser-San Francisco, San Francisco,
Calif., and Kaiser-San Rafael, San Rafael, Calif.) was received within
5 h of excision and was sectioned into 2- to 3-mm-thick blocks.
The tissue blocks were placed onto collagen sponges in the culture
medium as previously described (29), and 5 µl of clarified
virus-containing media was applied on top of these tissue blocks (0.1 to 0.5 ng of p24 or p27 for HIV-1, HIV-2, and SIVsmm primary isolates
and up to 5 ng of p24 or p27 per tissue block for HIV-1, HIV-2, and
SIVmac recombinants) as described previously. Productive HIV infection
was assessed by measuring the amount of p24 and p27 antigen that had
accumulated in the culture medium during the 3 days between successive
changes of medium. Infections in the depletion-kinetics experiment (see Fig. 2) were performed with 5 µl of virus-containing media per tissue
block, which represented 7 to 40 50% tissue culture infectious doses
as determined by terminal dilution of the virus stocks in quadruplicate
on heterologous phytohemagglutinin-activated PBMC propagated with human
IL-2 (5 U/ml).
Assessment of CD4+ T-cell depletion by FACS
analysis.
On day 12 following infection, cells were mechanically
isolated from infected and uninfected control tissue and analyzed by flow cytometry (fluorescence-activated cell sorting [FACS]).
Dispersed cells from infected and uninfected lymphoid histocultures
were stained for cell surface markers CD3, CD4, CD8, and CCR5 as
described previously (29, 34), by using the following
monoclonal antibodies: anti-CD3 (clone SK7, phycoerythrin conjugated),
anti-CD4 (clone SK3, fluorescein isothiocyanate conjugated), anti-CD8
(clone SK1, PerCP conjugated) (Becton Dickinson) and anti-CCR5 (clone
2D7, antigen-presenting cell conjugated) (Pharmingen). Then, 10,000 lymphocytes positive for CD3 surface marker were counted and the data
were analyzed with CELLQUEST software (Becton Dickinson). To facilitate
comparison among experiments, CD4+ T-cell depletion was
assessed by measuring the ratio of CD4+ to CD8+
T cells. This value was normalized to the CD4/CD8 ratio of control (uninfected) samples to yield the "mean relative CD4/CD8 ratio." Changes in the CD4/CD8 ratio represented CD4+ T-cell
depletion since increases in the numbers of CD3+
CD4
CD8 cells as a result of virus-induced
CD4 downregulation were insignificant in infected cultures.
Assessment of coreceptor utilization of SIVsmm isolates.
GHOST cells (NIH AIDS Research and Reference Reagent Program)
expressing human CD4 and human chemokine receptors were plated overnight at 40,000 cells/well per 12-well plate. The following day,
the cultures were infected with 20 to 50 ng of p27 of SIVsmm. Four days
after infection, the cultures were harvested and assayed for green
fluorescent protein expression by flow cytometry as an indicator of infection.
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RESULTS AND DISCUSSION |
Coreceptor specificity correlates with the cytopathic phenotype of
HIV-2 strains in lymphoid tissue ex vivo.
In order to elucidate
the impact of viral coreceptor specificity on the cytopathic potential
of HIV-2, we infected lymphoid histocultures with a panel of HIV-2
isolates that were previously established to exhibit distinct
coreceptor utilization patterns in vitro (7, 26, 28). As
described previously (16, 29, 34), CD4+
T-lymphocyte depletion in infected cultures of human tonsillar or
adenoid tissue was monitored as an indicator of virus-induced cytopathicity. The cultures were harvested on day 12 following infection, at which time the tissue was dispersed and immunostained for
CD4 and CD8. FACS analysis was used to measure the ratio of CD4+ and CD8+ T cells in infected versus
uninfected cultures, and CD4+ T-cell depletion was detected
as a decrease of the CD4/CD8 ratio in infected cultures.
This analysis revealed striking differences regarding the cytopathic
potential among different HIV-2 isolates, segregating the HIV-2 strains
into two distinct phenotypes. The primary isolate A1958 depleted
CD4+ T cells very mildly, as reflected in the slightly
depressed CD4/CD8 ratio in infected cultures, whereas the primary
isolate 7924A and the T-cell-line-adapted strain CBL20 aggressively
depleted CD4+ T cells in these cultures, as reflected in
severely depressed CD4/CD8 ratios (Fig.
1A). These differences in cytopathicity
were observed despite similar replication kinetics of these viruses, as
measured by accumulation of HIV-2 p27 antigen in the culture media
between successive media changes (Fig. 1A, inset).
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FIG. 1.
The cytopathic phenotype of HIV-2 is linked to
coreceptor specificity in ex vivo lymphoid tissue. (A) CD4+
T-cell depletion in adenoid cultures by various HIV-2 strains and two
HIV-1 recombinants was assessed by FACS analysis on day 12 postinfection. Shown are mean relative CD4/CD8 ratios (n = 3) with the SEM. Previously reported coreceptor specificities are
indicated (7, 26, 28, 29). (Inset) Viral replication of the
HIV-2 isolates was monitored by assessing accumulation of p27 in the
culture supernatant between successive medium changes. (B) In the same
infection, depletion within the CCR5+ and the
CCR5 subsets of CD4+ T cells was analyzed by
multiparameter FACS on day 12 postinfection. Shown are mean relative
CD4/CD8 ratios (n = 3) with the SEM for
CCR5+ and CCR5 T cells.
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Interestingly, this marked distinction in cytopathic effect
corresponded to the difference in coreceptor preferences among
these
HIV-2 isolates (Fig.
1A). Specifically, the mildly cytopathic
strain
A1958 has the R5 phenotype, whereas the highly virulent
strains CBL20
and 7924A have the X4 phenotype. These results mirror
the pattern
typically found for HIV-1 infections in lymphoid tissue
(
16,
29,
34), which is demonstrated here for comparison
purposes with a
recombinant isogenic HIV-1 virus pair, NL4-3 and
49-5, differing solely
in reciprocal specificity for CXCR4 and
CCR5, respectively (
9,
29,
38). Whereas the R5 strain (49-5)
only mildly depressed the
CD4/CD8 ratio compared to uninfected
control tissue (Fig.
1A), the X4
isogenic counterpart (NL4-3)
aggressively depleted CD4
+ T
cells in these cultures, thereby recapitulating the dramatic
impact of
CXCR4 specificity on cytopathicity of HIV-1.
These results indicate that viral coreceptor specificity significantly
influences the cytopathic potential of HIV-2 in lymphoid
tissue.
Moreover, HIV-2 cytopathicity seems to be controlled in
a manner
very similar to that of HIV-1, with specificity for CXCR4
linked to an
aggressive depletion phenotype. Furthermore, since
both the
CXCR4-restricted HIV-2 strain (CBL20) and the multitropic
primary
isolate (7924A) aggressively depleted CD4
+ T cells in these
cultures, specificity for CXCR4 appears to be
sufficient to confer high
cytopathicity to HIV-2 as it does to
HIV-1.
X4 HIV-1 and HIV-2 isolates show similar kinetics of
CD4+ T-cell depletion.
To define further the
cytopathic potential of X4 strains of HIV-2, we performed a
side-by-side comparison of the kinetics of CD4+ T-cell
depletion by HIV-1 and HIV-2 in lymphoid histocultures (Fig.
2). Tonsil tissue was infected ex vivo
with comparable doses of the primary isolates HIV-2 7924A and HIV-1
12/86. Both isolates were derived from patients with advanced disease
and displayed expanded coreceptor usage in vitro, including specificity
for both CXCR4 and CCR5 (10, 28). Infected and uninfected
control tissue was harvested at various time points following
infection, and CD4+ T-cell depletion was assessed at each
time point. This comparison revealed that both the HIV-1 and the HIV-2
strains progressively and profoundly depleted CD4+ T cells
and that they did so with comparable kinetics (Fig. 2), revealing that
a lower cytopathicity is not an integral feature of HIV-2.
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FIG. 2.
Comparable and progressive depletion of CD4+
T cells by multitropic primary isolates of HIV-1 and HIV-2 in ex vivo
tonsil cultures. Ex vivo tonsil cultures were inoculated with the
primary HIV-1 isolate 12/86 and the primary HIV-2 isolate 7924A, and
CD4+ T-cell depletion was assessed by FACS analysis on
subsequent days (3, 6, 9, 13, and 16) postinfection. Shown are mean
relative CD4/CD8 ratios (n = 3) with SEM (*,
n = 2).
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Coreceptor specificity determines the target cell population for
CD4+ T-lymphocyte depletion by HIV-2.
To investigate
further the mechanism underlying the differential cytopathicity of
HIV-2 in lymphoid histocultures, we stratified the depletion analyses
into coreceptor-expressing subsets of CD4+ T cells.
Immunostaining of tonsil tissue and FACS analysis revealed that CXCR4
is expressed on the majority of CD4+ T cells (mean ± standard error of the mean [SEM], 88.5% ± 1.6%; n = 25), whereas CCR5 is expressed on a minor subset (mean ± SEM, 10.4% ± 0.8%; n = 25) (see also reference
17). Stratification of the T-cell depletion analysis
into CCR5+ (CXCR4+) and CCR5
(CXCR4+) CD4+ T-cell subsets revealed a
distinct depletion pattern for the HIV-2 isolates tested. The R5
isolate A1958 preferentially and efficiently depleted within the
CCR5+CD4+ subset, whereas the X4 strain HIV-2
CBL20 and the multitropic isolate HIV-2 7924A caused profound depletion
in both T-cell subsets (Fig. 1B). These results mirror those observed
with the R5 (49-5) and X4 (NL4-3) strains of HIV-1 (Fig. 1B); such
subset-specific effects are readily evident despite some degree of
overlap between the CCR5+ and CCR5 cell
populations in FACS (17). Thus, R5 strains of HIV-2 are highly cytopathic for CCR5-bearing CD4+ T cells, and X4
strains of HIV-2 are cytopathic for the larger set of CD4+
T cells that bear CXCR4, demonstrating that CD4+ T-cell
depletion by HIV-2 is highly controlled by coreceptor specificity.
Therefore, HIV-2 should be viewed as an intrinsically cytopathic virus,
with its overall effects on the T-cell pool determined by the
coreceptor properties of the particular viral strain and the cellular
expression pattern of CCR5 and CXCR4 within the CD4+ T-cell population.
An attenuated HIV-2 strain displays an R5 depletion phenotype in ex
vivo lymphoid tissue.
Earlier studies described an attenuated
HIV-2 strain (HIV-2 ST) isolated from an asymptomatic HIV-2-infected
individual in Senegal, West Africa, which exhibited a noncytopathic
phenotype in vitro as indicated by the absence of virus-induced cell
fusion or cell death in T-cell lines and peripheral blood lymphocytes (PBL) (23). A recent study has shown that the molecular
clone of this virus, HIV-2 ST/SXB1, which displays the biological
properties of the parent HIV-2 ST isolate (24), uses CCR5,
BOB, and Bonzo, but not CXCR4, as coreceptor (11). Based on
our finding that coreceptor preferences highly influence the cytopathic
phenotype of HIV-2 in peripheral lymphoid tissue, we hypothesized that
the apparent noncytopathic phenotype of HIV-2-ST/SXB1 as assessed in
T-cell lines or PBL is a direct consequence of its inability to use CXCR4.
To test this hypothesis, we infected tonsil cultures with HIV-2 ST/SXB1
as well as the X4 primary HIV-2 isolate 7924A and
the R5 primary HIV-2
isolate SLRHC for comparison purposes. Twelve
days following infection,
the tissue was harvested and CD4
+ T-cell depletion in
infected cultures was analyzed. As predicted,
both HIV-2 ST/SXB1 and
SLRHC depleted CD4
+ T cells only mildly, whereas the X4
strain 7924A depleted cells
quite aggressively (Fig.
3A). Furthermore, stratification of the
analysis into the CCR5
+ and CCR5
CD4
+ T-cell subsets revealed that HIV-2 ST/SXB1
preferentially but
potently depleted cells within the CCR5
+
CD4
+ T-cell pool, as did SLRHC (Fig.
3B), thus mirroring
the typical
depletion phenotype of other R5 HIV-2 and HIV-1 strains
(Fig.
1) (
16,
29,
34). This finding demonstrates that the
reported
noncytopathic and nonfusogenic properties of HIV-2 ST/SXB1 in
T-cell lines or PBL are likely a consequence of its coreceptor
specificity for CCR5 and its inability to use CXCR4, rather than
of an
intrinsically noncytopathic character. It is of interest
to note that
both HIV-2 ST/SXB-1 and SLRHC (Fig.
3) were derived
from an
asymptomatic individual, whereas HIV-2 A1958 (Fig.
1)
was isolated from
a patient who had progressed to AIDS. Therefore,
these results also
demonstrate that both early- and late-stage
R5 HIV-2 isolates are
similarly mildly cytopathic in secondary
lymphoid tissue in contrast to
X4 HIV-2 isolates, which further
highlights the dominant impact of
coreceptor specificity on CD4
+ T-cell depletion by HIV-2.
Together these findings imply that
the differential expression of CXCR4
and CCR5 in the lymphoid
tissues is a crucial factor for the distinct
cytopathic behavior
of R5 and X4 HIV-2 strains in our experiments. This
principle
is consistent with a recent study demonstrating that
infection
of rhesus monkeys with chimeric SHIV viruses carrying X4 or
R5
HIV-1 envelopes led to markedly different pathogenic effects in
various lymphoid tissues in vivo, which was interpreted as the
result
of differential expression of CCR5 and CXCR4 in the respective
tissues
(
19).
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FIG. 3.
An HIV-2 strain with attenuated cytopathicity in vitro
displays the typical depletion phenotype of R5 strains. (A) Tonsil
histocultures were inoculated with HIV-2 ST/SXB1, X4 HIV-2 isolate
7924A, and R5 HIV-2 isolate SLRHC. CD4+ T-cell depletion
was assessed on day 12 postinfection. Previously reported coreceptor
specificities are indicated (11, 28). Shown are mean
relative CD4/CD8 ratios (n = 3) with SEM. (Inset) Viral
replication was monitored by assessing accumulation of p27 in the
culture supernatant between successive medium changes. (B) In the same
infection, depletion within the CCR5+ and the
CCR5 subsets of CD4+ T cells was analyzed by
multiparameter FACS on day 12 postinfection. Shown are mean relative
CD4/CD8 ratios (n = 3) with SEM.
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SIV depletes CCR5+ CD4+ T cells in human
lymphoid tissue ex vivo.
SIV is closely related to HIV-2
(8), but exhibits an interesting difference regarding its
coreceptor utilization profile. SIV isolates from naturally infected,
disease-resistant sooty mangabey monkeys (SIVsmm from Cercocebus
torquatus atys), as well as SIV strains that cause disease in
rhesus macaque monkeys (SIVmac from Macaca mulatta),
universally use CCR5 as a coreceptor, and most strains exhibit
additional capacities to use the orphan receptors BOB and/or Bonzo
(7, 11, 12). In contrast to HIV-1 and HIV-2, however, SIV
does not typically evolve to exploit CXCR4 as a coreceptor in vivo,
although both macaque and sooty mangabey CXCR4 coreceptors have been
demonstrated to be permissive for HIV-1 entry in vitro (7).
In view of the close relationship of HIV-2 and its simian ancestor
SIVsmm, the differences and similarities in coreceptor dependence among
HIV-2 and SIV, and the host-dependent pathogenicity of SIV strains, we
compared the CD4+ T-cell depletion phenotype of several SIV
strains with that of HIV-2 in human lymphoid histocultures. It had been
established earlier that human PBMC support SIV infection
(13), and the cross-species infectivity of SIV was further
demonstrated by the productive infection of a laboratory worker
following accidental exposure to SIVmac (21). These factors
provide a rationale for evaluating these viruses in the human lymphoid
tissue system.
We therefore infected tonsil cultures ex vivo with two recombinant SIV
strains (SIVmac239 and SIVmac316) that are highly virulent
in rhesus
macaques and two primary SIVsmm isolates (SIVsmm FKl
and SIVsmm FBo)
that were isolated from naturally infected sooty
mangabeys. All four
SIV strains display specificity for CCR5,
BOB, and Bonzo as coreceptors
(
12,
30) (see Fig.
5). In addition,
we performed infections
with SIVmac239PS, a derivative of SIVmac239
that is impaired in BOB
utilization as a result of a single amino
acid substitution in the V3
region of the envelope (
30). For
comparison purposes we also
infected cultures with the X4 primary
HIV-2 7924A and the R5 HIV-2
isolate A1958. On day 12 postinfection,
infected and uninfected
cultures were harvested and analyzed.
FACS analysis revealed that all
SIVmac strains and the primary
SIVsmm isolates mildly depleted
CD4
+ T cells in these cultures (Fig.
4A and
5A),
despite robust replication
(Fig.
4A and
5A, insets). Thus, SIVmac and
SIVsmm isolates displayed
a cytopathic phenotype comparable to that of
the R5 HIV-2 A1958
strain (Fig.
4A) and R5 HIV-1 strain (Fig.
1A)
(
16,
29,
34),
but contrasting with the aggressive depletion
phenotype of the
X4 HIV-2 7924A (Fig.
4A). No significant
difference was observed
for the cytopathic potential of SIVmac239
and SIVmac239PS, demonstrating
that coreceptor specificity for BOB does
not enhance viral cytopathicity
in peripheral lymphoid tissue.
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FIG. 4.
Mild depletion of CD4+ T cells by
recombinant strains of SIVmac in ex vivo lymphoid tissue. (A) Ex vivo
tonsil cultures were inoculated with recombinant strains SIVmac239,
SIVmac316, and SIVmac239PS and primary HIV-2 isolates A1958 and 7924A.
CD4+ T-cell depletion was assessed by FACS on day 12 postinfection. Shown are mean relative CD4/CD8 ratios (n = 3) with SEM. Coreceptor preferences are indicated as described
previously (7, 12, 28, 30). (Inset) Viral replication was
monitored by assessing accumulation of p27 in the culture supernatant
between successive medium changes. (B) In the same infections, T-cell
depletion analysis was stratified into CCR5+ and
CCR5 CD4+ T-cell subsets by multiparameter
FACS. Shown are mean relative CD4/CD8 ratios (n = 3)
with SEM for CCR5+ and CCR5 T cells.
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FIG. 5.
Mild depletion of CD4+ T cells by primary
SIVsmm isolates in ex vivo lymphoid tissue. (A) Ex vivo tonsil cultures
were inoculated with primary SIVsmm isolates FKl and FBo.
CD4+ T-cell depletion was assessed by FACS on day 12 postinfection. Shown are mean relative CD4/CD8 ratios (n = 3) with SEM. (Inset) Viral replication was monitored by assessing
accumulation of p27 in the culture supernatant between successive
medium changes. (B) In the same infections, T-cell depletion analysis
was stratified into CCR5+ and CCR5
CD4+ T-cell subsets by multiparameter FACS. Shown are mean
relative CD4/CD8 ratios (n = 3) with SEM for
CCR5+ and CCR5 T cells. (C) Coreceptor
preferences of SIVsmm isolates FKl and FBo were established by
infection of GHOST cells stably expressing CD4 together with various
coreceptors. Shown is usage of alternative coreceptors relative to that
of CCR5.
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Stratification of the T-cell depletion analysis in the
CCR5
+ and CCR5
subsets of CD4
+ T
cells further revealed that the SIVmac and SIVsmm strains
preferentially
and rather potently depleted CCR5
+
CD4
+ T lymphocytes (Fig.
4B and
5B). This finding suggests
that the
mild overall CD4
+ T-cell depletion induced by
these viruses is a consequence of
relative inaccessibility of the
overall CD4
+ T-cell population for these viruses due to
restricted cellular
expression of CCR5. Furthermore, the coreceptor
specificity for
BOB and Bonzo does not significantly increase the
target cell
pool for depletion and/or enhance viral cytopathicity in
human
lymphoid tissue compared with that of viruses with restricted
specificity for CCR5. The expression patterns for BOB and Bonzo
in
human tissue have been not well established to date, but they
clearly
do not facilitate aggressive CD4
+ T-cell depletion by HIV-2
or SIV in human lymphoid tissue ex
vivo. This failure to augment
overall CD4
+ T-cell depletion is consistent with the in
vivo comparison of
SIVmac239 and SIVmac239PS that revealed no
significant contribution
of BOB utilization to viral replication or
pathogenesis in the
rhesus macaque model (
30) and mirrors
our finding that alternate
coreceptors do not have a major role in
T-cell depletion by HIV-1
(
34).
In summary, this study demonstrates that primary and
T-cell-line-adapted HIV-2 strains display distinct cytopathic
phenotypes
in peripheral human lymphoid tissue depending on
their coreceptor
specificities for CXCR4 or CCR5, respectively. As with
HIV-1,
specificity of HIV-2 for CCR5 alone or in combination with
additional
coreceptors such as BOB and Bonzo is linked to restricted
overall
CD4
+ T-cell depletion potential, while specificity
for CXCR4 is linked
to a highly virulent phenotype. As assessed in ex
vivo lymphoid
cultures, these cytopathic properties of HIV-2 are very
similar
to those of HIV-1, both quantitatively and qualitatively. We
also
demonstrate that recombinant and primary strains of SIV, which
are
genetically closely related to HIV-2 but typically do not
exploit CXCR4
as a coreceptor, displayed a rather mild cytopathic
phenotype in human
peripheral lymphoid tissue mirroring that of
R5 HIV-1 and HIV-2. We
further observed that an HIV-2 strain that
was previously recognized as
attenuated in vitro displays cytopathic
properties in lymphoid tissue
that are similar to these of R5
HIV-1, HIV-2, and SIV strains,
indicating that viral coreceptor
specificity represents a major
regulator of the biological heterogeneity
that has been reported for
different strains of HIV-2 (
1,
5).
Finally, we found that
coreceptor expression patterns determine
the target cell population for
CD4
+ T-cell depletion by HIV-2 and SIV, which further
emphasizes that
coreceptor specificity is a key determinant of
cytopathicity of
HIV-2 in mature lymphoid tissue. Together, our
findings strongly
suggest that a lower intrinsic cytopathic potential
does not underlie
the remarkably slower disease progression that is
described in
many HIV-2-infected individuals (
20,
25,
32,
40), since
diverse HIV-2 strains exhibited robust
CD4
+ T-cell depletion potential in lymphoid tissues ex vivo
that was
indistinguishable from that of HIV-1; of course, studies of
additional
HIV-2 isolates would be useful for establishing how
generalizable
these findings are relative to other viral
strains.
It is particularly notable that the viral load in the peripheral blood
of HIV-2-infected individuals typically is much lower
than that in
HIV-1-infected individuals. The viral load in vivo
is an indicator of
viral fitness, or replicative capacity, and
viral clearance in the
context of the particular host environment
and poorly defined viral
and/or host features. It is evident that
a different dynamic
equilibrium of host and virus is established
during infection with
HIV-2 compared with HIV-1 (
3,
31).
Therefore, the present
results strongly suggest that this equilibrium,
rather than the
cytopathic character of HIV-2 per se, is responsible
for the attenuated
effects of HIV-2 in vivo. We speculate that
key host immune responses
that are not apparent in short-term
ex vivo lymphoid cultures operate
in vivo to control HIV-2 infection
relatively efficiently, as has been
proposed previously (
41).
This conclusion should prompt
further investigation to elucidate
the basis of this distinct
virus-host relationship as a possible
foundation for strategies to
modulate these processes in patients
infected with HIV-1 and/or HIV-2.
| |
ACKNOWLEDGMENTS |
We thank Beatrice Hahn, Ruth I. Connor, and Robin Weiss for
kindly providing viruses; Bruce Chesebro for kindly providing plasmids;
and Dee J. Holthe, Cecilia Stewart, Claudette Delphis, Ursula Perotti,
Sharon Hall, Jaqueline Hylton, Nancy W. Abbey, Mark D. Weinstein, and
the surgical staffs at Kaiser hospitals (San Rafael, Calif., and San
Francisco, Calif.) and San Francisco General Hospital for generous
assistance in obtaining post-tonsillectomy samples. Recombinant IL-2
was the generous gift of Chiron Corporation. We acknowledge the
technical assistance of Eric Wieder and Lisa Gibson in the conduct of
these experiments and the assistance of Heather Gravois, John Carroll,
and Neile Shea in the preparation of the manuscript.
B.S. is supported by the Boehringer Ingelheim Fond. M.L.P. is supported
by the Biomedical Sciences Graduate Program, the California Universitywide AIDS Research Program, and the NIH Medical Scientist Training Program at UCSF. F.K. is supported by the Deutsche
Forschungsgemeinschaft (SFB466), and R.M.G. and E.H.P. are supported by
NIH grant P51 RR-0165. This work was supported in part by NIH grant
R01-AI43695 (M.A.G.) and the J. David Gladstone Institutes (M.A.G. and
R.M.G.).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Gladstone
Institute of Virology & Immunology, P.O. Box 419100, San Francisco, CA
94141-9100. Phone: (415) 695-3775. Fax: (415) 695-1364. E-mail:
mgoldsmith{at}gladstone.ucsf.edu.
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Journal of Virology, October 2000, p. 9594-9600, Vol. 74, No. 20
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
