By
From the * Theodor Kocher Institute, Bern CH-3000, Switzerland; Aaron Diamond AIDS
Research Center, New York 10016; § Biomedical Research Center, University of British Columbia,
Vancouver, British Columbia V6T-2Z3, Canada; and
Laboratory of Cellular Physiology and
Immunology, Rockefeller University, New York 10021
HIV-1 actively replicates in dendritic cell (DC)-T cell cocultures, but it has been difficult to demonstrate substantial infection of purified mature DCs. We now find that HIV-1 begins reverse transcription much more efficiently in DCs than T cells, even though T cells have higher levels of CD4 and gp120 binding. DCs isolated from skin or from blood precursors behave similarly. Several M-tropic strains and the T-tropic strain IIIB enter DCs efficiently, as assessed by the progressive formation of the early products of reverse transcription after a 90-min virus pulse at 37°C. However, few late gag-containing sequences are detected, so that active viral replication does not occur. The formation of these early transcripts seems to follow entry of HIV-1, rather than binding of virions that contain viral DNA. Early transcripts are scarce if DCs are exposed to virus on ice for 4 h, or for 90 min at 37°C, conditions which allow virus binding. Also the early transcripts once formed are insensitive to trypsin. The entry of a M-tropic isolates is blocked by the chemokine RANTES, and the entry of IIIB by SDF-1. RANTES interacts with CCR5 and SDF-1 with CXCR4 receptors. Entry of M-tropic but not T-tropic virus is ablated in DCs from individuals who lack a functional CCR5 receptor. DCs express more CCR5 and CXCR4 mRNA than T cells. Therefore, while HIV-1 does not replicate efficiently in mature DCs, viral entry can be active and can be blocked by chemokines that act on known receptors for M- and T-tropic virus.
The ability of HIV-1 to infect cultured dendritic cells
(DCs) is a subject of intense research. DCs are found
at body surfaces as well as in lymphoid organs, particularly
in T cell-rich regions. DCs are potent antigen-presenting
cells and act as adjuvants for immune responses in vivo.
Therefore DCs are critically positioned to pick up HIV-1
and deliver virus to CD4+ T cells. There is some controversy on the capacity of HIV-1 to infect cultured DCs. Efficient replication has been reported by some groups (1, 2)
but not by others (3). More uniform findings have been
reported when DCs are exposed to HIV-1 and then cultured together with T cells. Upon the interaction of the two cell types, extensive virus replication occurs (3, 4, 6).
In this paper, we present evidence that HIV-1 efficiently interacts with purified DCs relative to T cells, as long as the analyses consider the formation of early rather than later
stages of reverse transcription. We will present evidence
that the development of these early transcripts represents
entry of virus, and that chemokines that block M-tropic
and T-tropic coreceptors can inhibit the interaction of
HIV-1 with DCs.
Cells.
Mixtures of DCs and T cells were allowed to emigrate
from explants of human skin and sorted into DCs and small T cells
(6, 7, 9). DCs were also generated from blood monocytes using a
two-step culture protocol (10, 11). In brief, E rosette negative,
blood mononuclear cells were cultured 6-7 d in a mixture of
GM-CSF and IL-4 each at 1,000 U/ml. The nonadherent cells
then were replated in a monocyte conditioned medium (12) for 4 d. At day 11, the DCs were purified by sorting on a FACStarPLUS®
(Becton Dickinson and Co., Mountain View, CA). T cells were
E rosetted cells that were purified by passage over nylon wool. T
blasts were E rosetted cells stimulated with 1 µg/ml PHA (Burroughs Welcome) or 5 ng/ml SEE superantigen (Toxin Technologies) for 3 d either immediately after taking the blood, or after 7 d
of culture at 5 × 106 cells/ml. The medium was RPMI-1640
(GIBCO BRL, Gaithersburg, MD) with either 5-10% FCS or
1% autologous human plasma and antibiotics.
FACS®.
Binding of saturating doses of mAbs to CD83 (a
kind gift of Dr. Schmittling, Coulter Corp., Hialeah, FL) and
CD4 (Leu 3a; American Type Culture Collection [ATCC],
Rockville, MD) was visualized with goat anti-mouse Ig and a
FACScan® instrument. Binding of soluble gp120 (IIIB strain;
Repligen, Cambridge, MA) was assessed by adding 1 µg/ml for 1 h
on ice, followed by the 110.4 anti-gp120 mAb (13) (Genetic Systems Inc., Seattle, WA) and PE-goat anti-mouse Ig (Tago Immunologicals, Camarillo, CA). gp120 binding was carried out on
blood DCs and T cells (distinguished by light scattering, references 7, 9), or on skin cells.
HIV-1.
M-tropic isolates (Ba-L, JR-FL, SF162, ADA) and
the T- tropic isolate IIIB were from the AIDS Resources Program. HIV-1 was grown in mitogen stimulated PBMCs except
for IIIB, which was grown in the CEM T cell line. All viruses
were applied in 0.1 ml to 105 cells (multiplicity of infection
[MOI] of 0.01-0.1) for 90 min at 37°C in either round-bottomed
microtest wells or small Eppendorf tubes. To reduce the amount
of HIV-1 DNA in the virus supernatants, the latter were filtered
and treated with RNAse-free DNAse (50 U/ml; Boehringer
Mannheim Corp., Indianapolis, IN) for 30 min at room temperature in 10 mM MgCl2.
Dectection of Reverse Transcripts in Leukocytes Exposed to HIV-1.
To detect viral DNA, the virus-pulsed cells were washed once in
PBS and lysed in lysis buffer (10 mM Tris HCl, pH 8, 1 mM EDTA,
0.001% Triton X 100/SDS and 1 mg/ml proteinase K). The samples were incubated at 60°C for 1 h and then placed in a boiling
water bath to inactivate the protease. Quantitative PCR amplification was performed with one oligonucleotide of each complementary pair 5 Chemokines and Chemokine Receptors.
Several chemokines were
prepared by chemical synthesis (16) and stored frozen at 200 µM.
The chemokines were used at 100 nM and applied for 30 min to
cells before HIV-1 and then during exposure to virus. CCR5
cDNA, cloned into pcDNA3.1 vector using HindIII and Xho1 restriction enzyme sites, was a generous gift of Drs. T. Dragic and
J.P. Moore (ADARC, The Rockefeller University, New York)
(17). CXCR4 cDNA, also called LESTR (18) or fusin (19), was
inserted into pcDNA3 vector using EcoR1 sites. For Northern
analyses, we used a 380 bp CCR5 fragment, prepared by digestion with Kpn1 and HindIII, and a 600-bp CXCR4 fragment
prepared by digestion with BamH1. The 32P-labeled probes were
synthesizing using a random primed DNA labeling kit (Boehringer Mannheim) and used at 106 cpm/ml of hybridization
buffer with 6 µg of RNA from the different cell types described
above. Blood DCs, T cells, and T blasts were prepared from two
individuals (EU3 and EU5) who are homozygous for a 32-bp deletion in CCR5 and are resistant to HIV-1 infection (20).
Two types of DCs were studied with
comparable results. The more abundant were DCs that develop from blood progenitors during prolonged culture in
cytokines, including GM-CSF and IL-4 (10, 11). These
monocyte-derived DCs were purified from residual lymphocytes by sorting, selecting for large nonadherent cells that lacked B and T cell markers (Fig. 1 A). The second
source was DCs that emigrate along with T cells from human skin. These also were separated into DC and T cell
enriched populations by sorting (6, 7, 9). Greater than 95%
of blood and skin DCs expressed the CD83 DC-restricted
antigen (21, not shown). Both skin and blood-derived DCs
expressed CD4 and bound purified HIV-1 gp120, but
CD4 and gp120 binding were much less than T cells (Fig.
1 B).
HIV-1 was
applied to purified DCs and T cells from blood and skin for
90 min at 37°C, washed and recultured. At time points thereafter, DNA was amplified for HIV-1 containing sequences by PCR with described primers (14). We emphasized the R/U5 pair that detects early products of reverse
transcription and the LTR/gag pair that detects the final
stages.
At time 0, i.e., 90 min after adding virus to purified
blood DCs at 37°C, the signals for R/U5 DNA sequences
were weak or absent. HIV-1 DNA then increased steadily
for 8 h to reach a plateau (Fig. 2 A) for at least 1-3 d (not
shown). Only the early products of reverse transcription
were abundant. At the dose of virus we employed, and relative to a standard curve derived from the ACH-2 cell line
that expresses 1 copy of proviral DNA/cell (15), we observed 103-104 copies of R/U5 DNA in 100,000 DCs and
>102 copies of LTR/gag sequences (Fig. 2 A). This signal
is very high considering that we were only applied virus at
<0.1 MOI. R/U5 DNA was weak or not detected with
comparable numbers of purified T cells (Fig. 2 A). T blasts
were readily infected, as both R/U5 and LTR/gag containing sequences were found. The amount of these sequences increased rapidly in culture, because infection was productive in T blasts (Fig. 2 A).
Several different HIV-1 isolates entered and begin reverse transcription in DCs (Fig. 2 B). Using comparable
numbers of infectious units, the interaction of Ba-L, SF162
and IIIB was particularly efficient. Efficient entry of these
and other primary isolates was also noted in skin DCs,
more than skin T cells, but only with probes for R/U5 sequences (Fig. 2 C).
Given the evidence that HIV-1 virions can contain short
reverse transcripts (22, 23), we were concerned that the R/U5 sequences represented intraviron-DNA that had bound but
not entered the DCs. However, entry seemed more likely
for the following reasons. The R/U5 signal was weak
when virus was added on ice for 4 h (Fig. 2, D and E), even
though virus does bind in the cold (23). The R/U5 signals were weak if the cells were examined just after the 90min virus pulse at 37°C, but increased progressively for 8 h after washing away nonbound virus (Figs. 2, A and F). In
contrast, virus binding can be detected in just 3-5 min at
this temperature (23). The R/U5 signals that developed
after 4 h at 37°C also were insensitive to trypsin (Fig. 2, D
and E), which releases surface-bound virus (23). We confirmed that trypsin destroys the HIV-1 binding epitope on
CD4 that is identified with leu3a mAb (not shown).
The presumed entry of HIV-1 into DCs was
totally blocked with recombinant soluble CD4 or the
blocking leu 3a anti-CD4 antibody (not shown). The role
of chemokine coreceptors was first assessed with a panel of
chemokines as blockers. For both blood-derived DCs and
skin DCs, the entry of Ba-L was almost completely blocked by RANTES (Fig. 3, A and B) and less completely by
MIP-1
As mentioned, our uncloned preparation of IIIB which
is grown in the CEM T cell line, very efficiently entered
DCs. However entry of IIIB into blood and skin DCs was
partially blocked by SDF-1 and not RANTES (Fig. 3 B, left
panels). SDF-1 binds to CXCR4 and blocks entry of T-tropic
HIV-1 (28, 29). Therefore separate receptors mediate entry
of M-tropic isolates and IIIB into DCs.
To prove that CCR5 was the major receptor for entry of
M-tropic isolates into DCs, we prepared DCs from the
blood of two patients with nonfunctioning mutant CCR5
(20, 30). These DCs did not permit entry of Ba-L (Fig. 3 B,
right bottom) or SF162 (not shown). Entry of IIIB was efficient, however, and partially blocked by SDF-1 (Fig. 3 B,
left bottom).
The availability of large numbers of blood-derived DCs permitted
northern blots for chemokine receptor mRNA. We used
comparable amounts of RNA from FACS sorted DCs, nylon wool nonadherent T cells, E rosetted T cells stimulated
with IL-2 only or with PHA plus IL-2, and total peripheral
blood mononuclear cells (Fig. 4). With CCR5 probes,
CCR5 mRNA was detected in DCs but not in T cells.
IL-2 stimulated cells expressed CCR5 RNA. CXCR4
(also called fusin or LESTR, references 18, 19) mRNA was
abundant in both DCs and resting T cells (Fig. 4), but at
least 10 times more T cells were required to provide the
same amount of RNA as DCs.
In this paper, we present evidence that HIV-1 enters and
begins reverse transcription efficiently in DCs, particularly
when compared to T cells. Several studies on the susceptibility of purified DCs to HIV-1 in the last few years have
concluded that the virus infects DCs weakly if at all (3, 7).
Now we have obtained evidence that HIV-1 does enter
DCs. The DCs we studied are fully mature as evidenced by
expression of markers like CD83 and p55, high levels of
CD86, a lack of Fc receptors and CD1a. Entry of HIV-1
into these cells was only manifested by the presence of the
early products of reverse transcription. In prior work, the
presence of full length gag-containing sequences had been used to monitor infection.
We favor the idea that short R/U5 sequences indicate
viral entry, rather than transcripts present in added virions,
because of the need for elevated temperature and prolonged time to detect early transcripts, and once formed,
their insensitivity to trypsin. Possibly reverse transcription
takes place within virions after binding or endocytosis, but
without fusion and true entry into DCs (31, 32). We consider this less likely since it would mean that the DCs
would somehow have to provide the nucleotides and other
stimuli that are required for intravirion transcription (31, 32),
and that both CD4 and chemokine receptors would mediate binding to DCs but would not allow fusion and entry.
The basis for the more abundant early transcripts in DCs
relative to T cells could lie at the level of viral entry or the onset of reverse transcription. We have not directly studied
viral entry into DCs and T cells but only the formation of
early transcripts. The biological significance of these transcripts remains to be pursued, but we know that viruspulsed DCs initiate a vigorous infection upon coculture
with T cells. It now will be important to test if DCs harbor
genomic RNA and early transcripts in vivo.
Several chemokine receptors can mediate HIV-1 entry.
One is CCR5 that is blocked by RANTES (17, 26, 27)
and deleted in select patients (20, 30). This receptor mediates entry of M-tropic isolates into DCs, as in other cell
types. CXCR4 or fusin/LESTR is a second receptor that is
utilized by T-tropic isolates (19) and is blocked by SDF-1
(28, 29). This receptor seems to mediate entry of IIIB into
DCs, since IIIB is able to enters CCR5 deficient DCs, and
entry is reduced by SDF-1 a known ligand for CXCR4.
However, SDF-1 did not block entry of IIIB completely, in contrast to reports with other cells (28, 29), so other receptors may contribute to viral entry into DCs.
CCR5, the major receptor for M-tropic virus, seems
dispensable given the well being of the three individuals
who are known to lack CCR5. Because DCs seem important during transmission and chronic replication of immunodeficiency viruses (33), RANTES antagonists could provide a novel anti-HIV-1 therapy.
end-labeled with 32P. The samples were subjected
to 5 min of denaturation at 94°C followed by 25 cycles of denaturation for 1 min at 91°C and polymerization for 2 min at 65°C.
Amplified products were resolved on 8% nondenaturing polyacrylamide gels and visualized by direct autoradiography of the
dried gels. Primers were described by Zack et al. (14) and were as
follows: for R/U5 sense 5
-ggctaactagggaacccacgt-3
, antisense 5
-ctgctagagattttccacactgac-3
(amplification product, 140 bp) and
for LTR/gag sense 5
-ggctaactagggaacccacgt-3
, antisense 5
-cctgcgtcgagagagctcctctgg-3
(amplification product, 200 bp). HIV-1
copy numbers in 50,000 cells per lane were estimated by comparison with graded doses of ACH-2 cells, which contain one copy
of provirus per cell (15).
Sources of DCs.
Fig. 1.
Expression of the CD4 receptor for HIV-1 on DCs and T cells. (A) Criteria for sorting blood-derived DCs (circle) from residual T cells. Lymphocytes (low FSC) were labeled with anti-CD3 and anti-CD20; large FSC, negative cells were isolated (FACStarPlus®). (B) Expression of CD4 (mAb
leu3a) and binding of soluble gp120 (HIV-1 IIIB) to DCs and T cells from blood and skin.
[View Larger Versions of these Images (28 + 25K GIF file)]
Fig. 2.
Efficient entry of HIV-1 into DCs but not small T cells. The results are representative of 2 or more experiments in each case. (A) Early vs.
late stages of reverse transcription in blood-derived DCs. IIIB was added for 90 min at 37°C to DCs, purified T cells (T), and T blasts (TBl), washed, and
cultured 0, 4, 18, or 36 h. Early and late (R/U5 and LTR/gag primers) transcripts were amplified by PCR and compared to graded doses of ACH-2
cells. (B) Several isolates of HIV-1 efficiently enter blood-derived DCs. Graded doses of the denoted isolates (titred by the AIDS Resources Program)
were added to DCs for 90 min, washed, and cultured 4 h before amplifying R/U5 DNA.(C) Detection of early R/U5 transcripts 9 h after adding Ba-L
and IIIB isolates to skin leukocytes, either bulk skin cells (SC), FACS®-purified DCs and T cells, or a 1:2 DC/T mixture. (D and E) Evidence that early reverse transcripts in HIV-1 pulsed DCs represent viral entry and not simply binding to skin leukocytes (D) or blood derived DCs (E). R/U5 sequences are
infrequent if virus was bound for 4 h on ice, and was trypsin insensitive (0.25%, GIBCO for 10 min at 37°C after 4 cell washes in phosphate saline) if virus was offered for 4 h at 37°C. (D) Kinetics of R/U5 sequence formation with Ba-L or IIIB in skin cells (SC) and T blasts. The 0 h time point was carried
out 90 min after adding virus at 37°C. DNA was also analyzed 1-8 h after the virus pulse, washing, and culture.
[View Larger Versions of these Images (31 + 20 + 20 + 29 + 24 + 35K GIF file)]
, which are known ligands for the CCR5 coreceptor for M-tropic HIV-1 (17, 26, 27). No block of Ba-L
entry was observed with SDF-1, a ligand for the CXCR4
receptor for T-tropic isolates (28, 29). Several chemokines
did not block the entry of Ba-L (Fig. 3 A): the CC chemokines eotaxin, MCP-1 and MCP-3, and the CXC chemokines, IL-8,
IP-10, Mig, and PF-4.
Fig. 3.
Role of chemokine receptors for viral entry into DCs. (A)
DCs from blood were exposed to no blocker () or to 100 nM of the indicated chemokines for 30 min. Then Ba-L was added for 4 h before amplifying early R/U5 DNA sequences. In parallel (not shown), IIIB was
also studied and only SDF-1 was inhibitory. (B) DCs from blood (top) or
skin (middle) were exposed to Ba-L and IIIB in the presence of no blocker
(
) or 100 nM RANTES, MIP-1
, or SDF-1. The lower row shows R/U5
transcripts after adding Ba-L or IIIB to DCs from a CCR5 mutant individual.
[View Larger Versions of these Images (27 + 52K GIF file)]
Fig. 4.
Northern blots for
CCR5 (top) and CXCR4 (middle) mRNA in blood derived
DCs, T cells, and peripheral
blood cells. The exposure times
were 7 d for CCR5 and 5 h for
CXCR4. Results are representative of two separate experiments
performed with newly synthesized CCR5 and CXCR4
cDNA probes labeled to comparable intensity and applied to 6 µg of RNA/lane. Er+ cells were
cultured for 8 d with IL-2 (100 U/ml) ± PHA (1 µg/ml) prior
to RNA extraction.
[View Larger Version of this Image (54K GIF file)]
Address correspondence to Angela Granelli-Piperno, Laboratory of Cellular Physiology and Immunology, Rockefeller University, 1230 York Ave., New York, NY 10021.
Received for publication 19 September 1996
Richard Koup is an Elizabeth Glaser Scientist of the Pediatric AIDS Foundation.We are grateful for the contributions of Judy Adams, Anita Ready, Mary Feldman, and Nancy Gallo (New York FireFighters Skin Bank, New York Hospital).
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