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Journal of Virology, December 1998, p. 9788-9794, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Neutralizing Monoclonal Antibodies Block Human
Immunodeficiency Virus Type 1 Infection of Dendritic Cells and
Transmission to T Cells
Sarah S.
Frankel,1,2,*
Ralph M.
Steinman,3
Nelson L.
Michael,1
Silvia Ratto
Kim,1
Nina
Bhardwaj,3
Melissa
Pope,3
Mark K.
Louder,1
Philip K.
Ehrenberg,1
Paul W. H. I.
Parren,4
Dennis R.
Burton,4
Hermann
Katinger,5
Thomas C.
VanCott,1
Merlin L.
Robb,1
Deborah L.
Birx,1 and
John R.
Mascola1,6
Division of Retrovirology, Walter Reed Army
Institute of Research and Henry M. Jackson Foundation for the
Advancement of Military Medicine, Rockville,1
and
Department of Infectious Diseases, Naval Medical Research
Institute, Bethesda,6 Maryland;
Division
of AIDS and Emerging Infectious Diseases, Department of Infectious
and Parasitic Disease Pathology, Armed Forces Institute of
Pathology/American Registry of Pathology, Washington,
D.C.2;
Laboratory of Cellular Physiology
and Immunology, The Rockefeller University, New York, New
York3;
Department of Immunology and
Molecular Biology, The Scripps Research Institute, La Jolla,
California4; and
University of
Agriculture, Institute of Applied Microbiology, Vienna,
Austria5
Received 7 July 1998/Accepted 20 August 1998
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ABSTRACT |
Prevention of the initial infection of mucosal dendritic cells (DC)
and interruption of the subsequent transmission of HIV-1 from DC to T
cells are likely to be important attributes of an effective human
immunodeficiency virus type 1 (HIV-1) vaccine. While anti-HIV-1
neutralizing antibodies have been difficult to elicit by immunization,
there are several human monoclonal antibodies (MAbs) that effectively
neutralize virus infection of activated T cells. We investigated the
ability of three well-characterized neutralizing MAbs (IgG1b12, 2F5,
and 2G12) to block HIV-1 infection of human DC. DC were generated from
CD14+ blood cells or obtained from cadaveric human skin.
The MAbs prevented viral entry into purified DC and the ensuing
productive infection in DC/T-cell cultures. When DC were first pulsed
with HIV-1, MAbs blocked the subsequent transmission to unstimulated
CD3+ T cells. Thus, neutralizing antibodies can block HIV-1
infection of DC and the cell-to-cell transmission of virus from
infected DC to T cells. These data suggest that neutralizing antibodies could interrupt the initial events associated with mucosal transmission and regional spread of HIV-1.
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INTRODUCTION |
Dendritic cells (DC) at the mucosal
surface of the genital tract are likely to be the initial target of
human immunodeficiency type 1 (HIV-1) infection (19, 26, 33,
36). Intraepithelial DC express CD4 and the beta chemokine
receptor CCR5, which serve as coreceptors for HIV-1 cell entry
(46). During their normal function of immunosurveillance, DC
capture antigen, traffic to draining lymph nodes, and present antigen
to T cells. During migration to regional lymph nodes, the maturing DC
upregulates expression of immunostimulatory molecules such as B7.1
(CD80) and B7.2 (CD86). The mature DC then presents antigen to T cells
to initiate immunity (3, 8, 35, 37). While the exact
mechanism of mucosal transmission is unknown, HIV-1 appears to exploit
the normal DC pathway of antigen uptake and presentation to gain access
to the CD4+ T cells in the lymphoid tissue. In humans,
active replication of HIV-1 has been shown to occur in DC/T-cell
syncytia at the lymphoepithelial surface of tonsils (14),
adenoids (14, 15), and parotid glands and colon
(13a). In macaques, intravaginal inoculation with the simian
immunodeficiency virus appears to target DC in the lamina propria of
the cervicovaginal mucosa (36), and in vitro studies have
provided evidence for viral entry into DC (1, 7, 17, 18, 28)
and for viral replication in immature DC (5, 43).
Immature DC selectively replicate macrophage-tropic isolates of HIV-1
(16, 33, 46), while mature DC do not support HIV-1 replication until they are cocultured with CD4+ T cells
(1, 2, 7, 16, 17, 30-32, 44). In the mature DC/T-cell
culture system, robust HIV-1 replication occurs without mitogen
stimulation of T cells and without the addition of exogenous cytokines
(17, 32, 44). The DC/T-cell syncytia in these cocultures are
phenotypically similar to those observed in vivo (15, 30,
32). Recent studies have shown that freshly isolated (immature)
epidermal Langerhans cells expressed CCR5 but not CXCR4 on their
surface and that these cells fused with CCR5 (R5) but not CXCR4 (X4)
using HIV-1 envelopes (46). In addition, when HIV-1 strains
were applied to the abraded epidermal surface of skin organ cultures,
it was found that R5 viruses were selectively captured by DC that
emigrated from the explanted skin (33). These findings for
cultured DC indicate that DC may initiate HIV-1 transmission in vivo,
by capturing R5 HIV-1 and subsequently initiating viral replication in
T cells.
Neutralization of HIV-1 at the initial stages of virus entry might be a
critical determinant of vaccine efficacy. Most neutralization studies
have measured HIV-1 infection in mitogen- and interleukin-2 (IL-2)-stimulated T cells (11), a target cell type that may not participate in the initial events of infection. It is not known if
anti-HIV-1 antibody can prevent infection of mucosal DC or the
subsequent transmission of HIV-1 from DC to T cells. Since anti-HIV-1
antibodies that neutralize infection by primary HIV-1 isolates are
uncommon and are not readily elicited by most HIV-1 immunogens
(23), we studied three human monoclonal antibodies (MAbs)
(IgG1b12, 2F5, and 2G12) that potently neutralize infection of
activated T cells by primary HIV-1 isolates (6, 21, 39). As
a model for the interaction of HIV-1 with DC at mucosal surfaces and in
draining lymph nodes, we sought to determine if these MAbs could
prevent HIV-1 infection of pure DC as well as transmission of HIV-1
from infected DC to unstimulated T cells. Using blood and skin DC, we
found that anti-HIV-1 neutralizing MAbs can block both virus entry into
DC and the transmission of HIV-1 from infected DCs to T cells. These
data suggest that anti-HIV-1 neutralizing antibodies could interrupt
the mucosal transmission and regional spread of HIV-1 and that a
vaccine eliciting neutralizing antibody could prevent mucosal
transmission of HIV-1.
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MATERIALS AND METHODS |
Preparation of blood DC.
DC were generated from the blood of
normal donors by using protocols similar to those previously reported
(4, 34). Peripheral blood mononuclear cells (PBMC) obtained
by Ficoll-Hypaque sedimentation were depleted of CD3+ T
cells by two incubations with anti-CD3 immunomagnetic beads (Dynal
Inc., Great Neck, N.Y.). The T-cell-depleted leukocytes were adhered to
immunoglobulin G (IgG)-coated plastic flasks, and nonadherent cells
were vigorously removed by four washes with phosphate-buffered saline.
Adherent cells were maintained for 7 days in culture medium (RPMI 1640 medium supplemented with 15% heat-inactivated fetal calf serum, 100 U
of penicillin per ml, 100 µg of streptomycin per ml, and 2 mM
L-glutamine) containing 1,000 U each of recombinant human
IL-4 (R&D Systems, Minneapolis, Minn.) and granulocyte-macrophage
colony-stimulating factor (Immunex, Seattle, Wash.) per ml. Cytokines
were replenished on alternate days. On day 7, culture medium was
replaced with macrophage conditioned medium (MCM) that was also
supplemented with 1,000 U each of granulocyte-macrophage colony-stimulating factor and IL-4 per ml. To prepare MCM, PBMC were
adhered to IgG-coated plastic flasks in culture medium containing 10%
heat-inactivated normal human serum. After removal of nonadherent cells, the MCM supernatant was collected daily for 5 days. Cell-free supernatant was analyzed for the level of tumor necrosis factor alpha
by enzyme-linked immunosorbent assay (R&D Systems), and medium
containing 50 IU or more was used as MCM. Mature DC were harvested for
use on day 11 and resuspended in culture medium without supplemental
cytokines. Purified CD3+ T cells were obtained by positive
selection from PBMC as described above, using anti-CD3 immunomagnetic
beads according to manufacturer's instructions. Viability of
cryopreserved purified CD3+ T cells was routinely 
90%;
the cells did not proliferate when returned to culture.
Skin-derived DC.
Skin-derived DC and T cells were obtained
from split-thickness skin harvested from cadavers within 12 h of
death (Lifenet, Virginia Beach, Va.) as previously described
(29-31). Briefly, skin explants were placed dermal side
down in 150-ml tissue culture dishes (Corning Plastics, Corning, N.Y.)
in 45 ml of culture medium. The skin was cultured for 2 to 4 days, and
the migrated cells were treated with collagenase D (Boehringer
Mannheim), washed, and resuspended in culture medium. Skin leukocytes
from this organ culture method contain a mixture of DC and
CD3+ T cells and are permissive for HIV-1 replication
(29, 30, 32). To obtain pure skin DC, skin leukocytes were
depleted of CD3+ T cells by using anti-CD3-coated
immunomagnetic beads as described above.
Flow cytometry.
DC were characterized by two-color staining
with fluorescein isothiocyanate- and phycoerythrin-conjugated mouse
MAbs, using a FACScan flow cytometer (Becton Dickinson, San Jose,
Calif.). The MAbs used were anti-HLA-DR, anti-CD80, anti-CD86,
anti-CD3, anti-CD14, anti-CD19, and anti-CD45 (Becton Dickinson);
anti-CD83 (Immunotech, Miami, Fla.); and anti-CD1a (PharMingen, San
Diego, Calif.) and isotype-matched controls. CD45-negative events were excluded from the fluorescence-activated cell sorting analysis.
Immunohistochemical staining of cytospin preparations.
Cell
cytospins were prepared as previously described (14, 31,
32). The primary antibodies were anti-HLA-DR, anti-CD3, anti-CD4,
anti-CD8, anti-CD20, anti-CD68, anti-S-100, and anti-HIV-1 p24gag (DAKO, Carpinteria, Calif.) and
anti-CD1a, anti-CD80, and anti-CD83 (Immunotech). Cytospins of infected
DC/T-cell cultures were prepared between 2 and 11 days after exposure
to HIV-1.
Virus stocks.
HIV-1 isolates BaL, 89.6, and IIIB were
obtained from the NIH AIDS Reference and Reagent Repository, and
isolates US1 and SG365 were from the repository of the U.S. Military
HIV Research Program. Virus stocks were prepared by infection of
phytohemagglutinin (PHA)-stimulated PBMC as previously described
(22). BaL, US1, and SG365 are primary R5 viruses. HIV-1 89.6 is known to use both CCR5 and CXCR4 (10), and IIIB is a
T-cell line-adapted (TCLA) virus (12). BaL, US1, and IIIB
have been previously characterized as genetic subtype B, and SG365 has
been characterized as genetic subtype C (20). SG365 is
resistant to neutralization by the MAbs that we tested (unpublished data).
Antibodies.
Anti-HIV-1 human MAbs IgG1b12, 2F5, and 2G12
were chosen because each can block infection of PHA-stimulated PBMC
target cells by primary isolates of HIV-1 (6, 39, 40). MAb
2F5 recognizes the gp41 sequence ELDKWA (9, 27); MAbs 2G12
and IgG1b12 bind to different conformationally sensitive epitopes on
gp120 (6, 40). A control nonneutralizing MAb (4.8D) was
obtained from the NIH AIDS Reference and Reagent Repository (donated by
James Robinson). MAb 4.8D binds to a conformational epitope on gp120 but does not neutralize primary HIV-1 isolates at concentrations of up
to 50 µg/ml (11). All four MAbs are isotype IgG1.
DC infection and antibody neutralization assays.
Virus
infection and neutralizing antibody experiments with DC were performed
by using methodologies similar to those previously described for
PHA/IL-2-stimulated PBMC (21, 22). Blood DC harvested on day
11 were washed, resuspended in culture medium, and exposed to 500 50%
tissue culture infectious doses (TCID50) of virus per
5 × 104 cells (multiplicity of infection [MOI] = 0.01) in triplicate wells. DC were exposed to virus overnight, or for
90 min as noted, and then washed. For neutralization experiments, virus
and antibody were preincubated for 30 min at 37°C prior to the
addition of DC. Since mature DC replicate HIV-1 only in the presence of
T cells, positively selected CD3+ cells were added back to
the DC (2:1 ratio of CD3+ cells to DC). Virus replication
was monitored by enzyme-linked immunosorbent assay measurement of p24
antigen produced in culture supernatants. Neutralization was assessed
at days 6 to 8 for DC/T cells, or days 4 to 6 for PHA/IL-2-stimulated
PBMC, representing the early kinetics of virus growth. Neutralization
experiments with skin DC (depleted of CD3+ T cells) were
performed in a similar manner.
Molecular detection of viral entry and proviral formation.
A
semiquantitative PCR measurement of early and late HIV-1 reverse
transcripts in cell lysates was used to assess viral entry and proviral
formation, respectively, based on a modification of published
techniques (17, 45). Briefly, viral supernatant was
centrifuged at 900 × g for 10 min, filtered through a
0.22-µm-pore-size filter, and treated with RNase-free DNase (50 U/ml;
Boehringer Mannheim Corp., Indianapolis, Ind.). DC were exposed to
virus (MOI = 0.01) for 90 min at 37°C, washed to remove
unabsorbed virus, and then cultured alone or with CD3+ T
cells. Cell lysates from approximately 25,000 cells were separately amplified with 32P-end-labeled sense oligonucleotides to
generate 108- and 204-bp products representing early and late viral
reverse transcripts, respectively. Equivalent amounts of lysate were
subjected to amplification with 32P-end-labeled primers
specific for the single-copy gene CCR5 (25). PCR products
were resolved on 8% nondenaturing polyacrylamide gels and quantitated
by using storage phosphor technology. Copy numbers were computed by
comparison to a calibrated series of ACH-2 cell lysates which contain a
single provirus per cell (13) and then normalized for cell
input by reference to CCR5 signal intensity.
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RESULTS |
Purified mature DC do not become productively infected with HIV-1
but can transmit HIV-1 to unstimulated T lymphocytes.
We generated
mature blood DC from adherent CD14+ PBMC. Since our methods
were slightly different than those described (4, 34), we
reconfirmed that mixtures of mature DC and T cells, but not pure DC or
T cells alone, are permissive for HIV-1 replication (17,
30-32). After culture in cytokines, the DC developed into a
uniform population of large cells with typical processes, with both
veils and dendrites. They maintained this morphology despite the
withdrawal of exogenous cytokines on day 11. The population was
homogeneous by cytofluorometry and by immunocytochemical stains on
cytospins. Less than 1% of the cells expressed CD14, CD19, CD56, or
CD3. The cells expressed high levels of HLA-DR, the immunostimulatory molecules CD80 and CD86, and the DC marker CD83. Functionally, the DC
were potent stimulators of an allogeneic mixed leukocyte response,
inducing strong lymphoproliferative responses with 100- to
1,000-fold-fewer cells than PBMC stimulators (data not shown). Thus,
these DC fulfill the phenotypic and functional criteria for mature DC
(35). When exposed to HIV-1 BaL, neither mature DC alone nor
CD3+ T cells alone became productively infected. However,
robust HIV-1 replication was observed if CD3+ T cells were
added to DC that had been pulsed with HIV-1 and washed (Fig.
1).
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FIG. 1.
Infection kinetics of purified DC cultured in the
presence and absence of T cells. The DC were exposed to HIV-1 BaL (500 TCID50/105 DC) overnight at 37°C, thoroughly
washed to remove free virus, and cultured alone or with positively
selected CD3+ T cells. PHA/IL-2-stimulated PBMC and
unstimulated CD3+ cells were infected in a similar manner.
No p24 antigen expression was detected in purified DC or
CD3+ T cells alone. Robust infection, close to that seen
with activated PBMC, was detected when T cells were added to infected
DC. During infection, DC and CD3+ cells were cultured in
medium without exogenous cytokines. PBMC were maintained in culture
medium supplemented with 20 U of IL-2 per ml.
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Neutralizing MAbs inhibit productive infection of DC/T-cell
cocultures.
Preliminary data showed that HIV-1 BaL infection of
PBMC targets was abrogated (95 to 99% neutralization) by MAb IgG1b12
(25 to 50 µg/ml) or by the combination of MAbs 2G12 and 2F5 (each at
25 µg/ml). MAbs 2F5 and 2G12 were less potent individually than in
combination. Thus, MAb IgG1b12 and the combination 2F5/2G12 were used
for DC neutralization experiments. The neutralization dose-effect
curves for IgG1b12, 2F5/2G12, and the nonneutralizing MAb 4.8D, using
PBMC or DC targets, are shown in Fig. 2A and
B, respectively. No productive infection
was seen in DC/T-cell cultures when MAbs IgG1b12 and 2F5/2G12 were
preincubated with BaL at concentrations of >10 µg/ml. These
experiments were repeated several times with similar results. The 90 and 99% inhibitory concentrations for MAbs were approximately 5- to
10-fold lower when DC were use as targets than when activated PBMC were
used. Antibody-mediated virus neutralization in DC/T-cell cultures was
confirmed by immunocytochemical analysis of cultured cells. The p24
antigen found almost entirely in small and large syncytia in the
cultures was uniformly absent in cytospins of DC/T-cell cultures when
BaL had been preincubated with MAb IgG1b12 (Fig. 2C).
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FIG. 2.
(A and B) Antibody-mediated neutralization of HIV-1 BaL
infection of PHA/IL-2 stimulated PBMC (A) and DC (B), with
CD3+ cells added on day 1 after exposure of DC to HIV-1.
MAb IgG1b12, or the combination 2F5/2G12, was preincubated with virus
at a starting concentration (for each MAb) of 50 µg/ml prior to
addition of PBMC or DC. Extracellular p24 antigen was measured in the
early viral growth phase for PBMC (day 4) and DC/T cells (day 7).
Identical concentrations of the nonneutralizing MAb 4.8D did not
inhibit viral infection of PBMC or DC targets. (C) Immunocytochemical
staining of DC/T-cell cytospins for p24 antigen expression (brown) and
HLA-DR (purple). The right-hand panel shows a p24-positive syncytium on
day 7 after DC exposure to BaL (magnification, ×200). No
HIV-1-infected cells were seen when BaL was preincubated with 25 µg
of MAb IgG1b12 per ml (left, p24 antigen stain only; ×160).
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To evaluate neutralization of other HIV-1 strains, experiments were
performed with the TCLA virus IIIB, the dualtropic strain
89.6, and a
primary R5 isolate, US1. With the MAb combination
2F5/2G12, greater
than 99% neutralization of all four viruses
was seen, although
infection of DC by US1 was not completely prevented.
As a control for
possible nonspecific MAb effects on cell growth,
we used a clade C
virus (SG365) previously shown to be insensitive
to neutralization by
2F5/2G12. SG365 infection of DC/T-cell cultures
was not neutralized by
2F5/2G12 (Fig.
3).
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FIG. 3.
Neutralization of four clade B HIV-1 isolates by the
combination 2F5/2G12 (each at 25 µg/ml). Target cells were DC with T
cells added back as in Fig. 1. Stippled bars indicate preincubation of
DC with MAbs; gray bars show virus growth without antibody. The clade C
isolate (SG365) was not neutralized by 2F5/2G12.
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Neutralizing MAbs block entry of HIV-1 into DC.
To determine
if neutralizing MAbs block entry of HIV-1 into DC, we quantitated early
and late HIV-1 reverse transcripts present in cell lysates by PCR. As
shown in Fig. 4, HIV-1 BaL was incubated with DC or PBMC, and early and late transcripts were amplified at 0, 6, 36, and 96 h after infection. Similar to findings in a previous
report (17), only early transcripts were detected in pure
cultures of mature DC, whereas both early and late reverse transcripts
were detected in DC/T-cell cultures and activated PBMC. Preincubation
of BaL with the MAb combination 2F5/2G12 (each at 25 µg/ml) blocked
the formation of early reverse transcripts in pure DC (Fig. 4A). The
weak or undetectable early transcript signal at 6 and 36 h after
DC infection indicates the lack of effective viral entry. As expected,
2F5/2G12 also blocked the formation of late transcripts in DC/T-cell
and PBMC cultures. In a separate experiment, similar data were obtained
with MAb IgG1b12 (25 µg/ml) used in place of 2F5/2G12 (data not
shown).
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FIG. 4.
Neutralizing MAbs block virus entry into DC. Purified
blood DC were exposed to a DNase-treated, cell-free virus stock (HIV-1
BaL; MOI = 0.01) in the presence or absence of MAb combination
2F5/2G12 (each at 25 µg/ml) and subsequently incubated alone (DC) or
in the presence of purified CD3+ T cells (DC/TC). Parallel
control infections of PHA/IL-2-stimulated PBMC were also conducted.
Cell lysates were prepared at the times indicated postinfection and
amplified with 32P-labeled primers specific for early and
late HIV-1 reverse transcripts and for CCR5. Parallel amplification of
known numbers of ACH-2 cells (which contain a single integrated HIV-1
provirus per cell) were performed with each primer set to provide a
copy number quantitation curve. (A) Early reverse transcripts (RU5 long
terminal repeat [LTR] region sequences). (B) Late reverse transcripts
(LTR/gag). Arrows indicate the positions of specific
signals; the remaining visible bands are nonspecific (i.e., no late
reverse transcripts were seen in PBMC until the 36-h time point). (C)
CCR5 gene amplification (cell number control).
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Neutralizing MAbs block transmission of HIV-1 from infected DC to
unstimulated T cells.
It might be difficult for immunization to
elicit an effective concentration of neutralizing antibody at mucosal
surfaces where HIV-1 first interacts with DC. Thus, we sought to
determine if neutralizing MAbs could interfere with transmission of
HIV-1 from infected DC to unstimulated T cells, an event which may be
relevant to the initial transmission of HIV-1 in draining lymph nodes. Blood or skin DC were pulsed with HIV-1 BaL for 90 min at 37°C, extensively washed, and returned to culture. MAb was added to the
culture 24 h later, and T cells were added 30 min after antibody. On blood DC (Fig. 5A), MAb IgG1b12
blocked the transmission of BaL from purified, infected DC (which
contained early reverse transcripts) to T cells. In the absence of
neutralizing antibody, these same DC established a vigorous infection
when combined with T cells. When T cells were obtained from a donor
homozygous for the 32-bp deletion in the CCR5 gene, a coreceptor defect
known to abrogate infection with CCR5-using HIV-1 strains, there was no
propagation of HIV-1 infection. This finding demonstrates that transmission of infection from DC to T cells was CCR5 dependent. Prior
work has shown that functional CCR5 is needed on both DC and T cells to
obtain a productive HIV-1 infection with R5 viruses (16). To
test the ability of MAbs to prevent HIV-1 transmission from skin DC to
T cells, we used skin DC depleted of CD3+ cells. Similar to
results of experiments with blood DC, pure skin DC replicated virus
only upon addition of CD3+ cells to the culture (Fig. 5B).
Neutralizing MAbs completely blocked transmission of HIV-1 infection to
T cells by skin DC that had been pulsed with HIV-1.
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FIG. 5.
Neutralizing MAbs prevent the transmission of HIV-1 from
infected DC to T cells. Purified blood (A) or skin (B) DC were exposed
to HIV-1 BaL for 90 min and washed to remove free virus. MAbs were
added 24 h later. After a 30-min incubation, CD3+ T
cells were added to the culture. (A) MAb IgGb12 was used at 25 µg/ml.
As a control, CD3+ cells from a known homozygous CCR5
( /) donor were also used. Transmission of infection from DC to T
cells was dependent on CCR5 and could be blocked by neutralizing MAbs.
wt, T cells wild type for the CCR5 gene. (B) MAbs were used at a
concentration of 25 µg/ml.
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DISCUSSION |
The protective mechanisms of immunoglobulin at mucosal surfaces
are likely to be complex. Both locally produced IgG and IgA and
transudative IgG could play a role in protective immunity (24). In this study, we used IgG MAbs along with blood and
skin DC to model the interaction of antibody, HIV-1, and DC at mucosal surfaces and in lymphoid tissue. Three HIV-1 envelope-specific human
IgG MAbs were studied because they were previously shown to neutralize
HIV-1 infection of activated T cells. Our data show that these MAbs
prevent HIV-1 infection of pure DC and block the transmission of HIV-1
from infected DC to unstimulated T cells. Neutralization dose-response
data demonstrated potent antibody-mediated virus neutralization when
pure DC were used as targets of infection. MAb concentrations of 10
µg/ml resulted in complete neutralization of virus infection in the
DC cultures. The reason that inhibition of HIV-1 infection of DC
occurred at antibody concentrations lower than required to block
infection of mitogen-stimulated T cells is not clear. Additional
experiments are in progress to carefully monitor replication kinetics
in each culture system, using virus titered on each target cell
(47). When DC were exposed to HIV-1 in the presence of
neutralizing MAb, immunocytochemical staining of DC/T-cell cultures
showed no p24-positive DC/T-cell syncytia. In comparison, and as
previously described (30-32), multiple DC/T-cell syncytia
were seen on cytospins from cultures of DC exposed to HIV-1 in the
absence of MAb. We also tested the neutralizing activity of MAbs
against HIV-1 strains other than HIV-1 BaL. Potent neutralization was
demonstrated for a TCLA strain, a dualtropic (R5 and X4) virus, and a
clinical R5 isolate (IIIB, 89.6, and US1, respectively). Thus, these
MAbs appear to show broad anti-HIV neutralizing activity on DC targets,
as they do on PBMC targets. Prior studies have shown that HIV-1
efficiently enters mature DC, but only early products of reverse
transcription are produced until T cells are added to the culture
(16, 17). We confirm these data and show that neutralizing
MAbs block viral entry, as assessed by the absence of early reverse
transcripts in pure DC cultures.
While our initial experiments focused on the ability of antibody to
block virus entry into purified DC, it may be more relevant to mucosal
HIV-1 infection to determine if antibody can block transmission of
HIV-1 from an infected DC to a resting T cell. We modeled this
interaction by treating HIV-1-pulsed DC with MAb prior to the addition
of unstimulated T cells and observed no virus replication. Results were
similar for blood-derived and skin DC. These data suggest that if
luminal antibodies fail to prevent the initial interaction of HIV-1
with DC, antibodies present at draining lymph nodes could interrupt
DC-to-T-cell transmission. Several groups have studied the mechanism of
DC-to-T-cell HIV-1 transmission (5, 16, 17, 41, 44).
Granelli-Piperno and colleagues recently showed that functional CCR5 on
both DC and T cells was required for DC to infect T cells
(16), and Weissman et al. reported that transmission from
HIV-1-pulsed DC to T cells could be blocked by anti-CD4 antibody
(44). Our data confirm that transmission to T cells is
dependent on CCR5 and are the first to show that HIV-1 transmission to
DC can be blocked by HIV-1 envelope-specific antibody. Taken together,
these results suggest that neutralizing MAbs are blocking DC-to-T-cell
transmission via established mechanisms, i.e., by blocking virus
binding to CD4 or CCR5 or by inhibiting gp41-mediated cell fusion
(38, 42). Our results are limited to IgG HIV-1
envelope-specific MAbs and do not address the role of IgA at mucosal
surfaces (24).
In summary, our data demonstrate that anti-HIV-1 neutralizing
antibodies block HIV-1 entry into DC, the likely first cells infected
at the mucosal surface. In addition, neutralizing antibodies block the
in vitro transmission from HIV-1-infected DC to unstimulated T cells,
indicating that antibody could interrupt the initial spread of HIV-1 in
draining lymph nodes. These data suggest that both mucosal and systemic
immunoglobulin could play a role in prevention of sexual transmission
of HIV-1, thus supporting the rationale that generation of a
neutralizing antibody response will be an important component of an
effective HIV-1 vaccine.
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ACKNOWLEDGMENTS |
We thank Thach Bui, Marc Martin-ez, Poonam Mannan, and Robert
McLinden for excellent technical assistance, Lifenet (Virginia Beach,
Va.) for providing skin, and John McNeil, John Moore, Mark Lewis, and
Francine McCutchan for helpful discussions.
This work was supported in part by NIH grants HL59718 (J.R.M.), AI33292
(D.R.B.), and AI40874 (R.M.S.) and by cooperative agreement DAMD17-93-V
3004, between the U.S. Army Medical Research and Materiel Command and
the Henry M. Jackson Foundation for the Advancement of Military Medicine.
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FOOTNOTES |
*
Corresponding author. Mailing address: Walter Reed Army
Institute of Research, 13 Taft Court, Suite 200, Rockville, MD 20850. Phone: (301) 217-9410. Fax: (301) 762-4177. E-mail:
sfrankel{at}hiv.hjf.org.
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Abstract
Introduction
