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Journal of Virology, October 2000, p. 9328-9332, Vol. 74, No. 19
Istituto di Malattie Infettive e Tropicali,
Università di Milano, Ospedale Luigi Sacco, Milan,
Italy1; Infectious Disease Division,
Massachusetts General Hospital and Harvard Medical School,
Boston,2 and Infectious Disease,
Molecular Biology-Gene Expression, Genetics Institute Inc.,
Cambridge,3 Massachusetts; and
Departement de Biochimie Medicale, Centre Medical
Universitaire, Geneva, Switzerland4
Received 18 May 2000/Accepted 7 July 2000
We studied the combined anti-human immunodeficiency virus
type 1 (HIV-1) effects of a derivative of stroma-derived
factor 1 In 1995, Cocchi et al. reported
potent in vitro human immunodeficiency virus type 1 (HIV-1) inhibition
by three chemokines secreted by CD8+ T lymphocytes
(4) and focused attention on this class of molecules with
low molecular masses (8 to 12 kDa). The chemokines described, RANTES,
macrophage inflammatory protein-1 Relationships among membrane coreceptors, chemokines, and cellular
tropism were further defined in 1996 by Feng et al., who described a
novel molecule which acted as a cofactor for T-cell-tropic HIV-1
isolates but not for macrophage-tropic isolates (14). This
receptor, which was already known but did not have an identified natural ligand, belongs to the C-X-C chemokine receptor superfamily and
was named "fusin," or CXCR4. The receptor for HIV-1
macrophage-tropic isolates was subsequently identified and named C-C
chemokine receptor 5 (CCR5). CCR5 reacts with the chemokines RANTES,
MIP-1 During the early phases of HIV-1 infection, R5 viral strains usually
predominate, whereas X4 strains frequently emerge in the late stages of
HIV-1 infection, accompanied by a decline in peripheral blood CD4
lymphocytes and a clinical progression toward AIDS (7, 34).
Viral isolates with a dual tropism could represent a transition phase
between viral R5 and X4 phenotypes, or they may represent X4 viruses
that have maintained an ability to infect macrophages (31,
33).
The aim of our study was to evaluate the interactions between
attachment and entry inhibitors of HIV-1 infection. Our experiments suggest that the use of combined inhibitors of R5 and X4 viruses may be
useful in inhibiting mixed infections.
(This work was presented in part at the 7th Conference
on Retroviruses and Opportunistic Infections, San Francisco,
Calif., 30 January to 2 February, 2000 [S. Rusconi, S. La Seta
Catamancio, P. Citterio, E. Bulgheroni, F. Croce, S. H. Herrmann,
R. E. Offord, M. Galli, and M. S. Hirsch, Abstr. 7th Conf.
Retroviruses Opportunistic Infect., abstr. 501, 2000].)
Analysis of cellular tropism of the different viral isolates on
transformed cell lines.
The two viral isolates examined in this
study, RM and DK, were derived from two patients with primary HIV-1
infection acute syndrome (29), and the isolates were used to
infect U87MG-transformed CD4+ cells transfected with CCR5
or CXCR4 coreceptors (8), provided by Dan R. Littman (The
Skirball Institute of Biomolecular Medicine, New York University School
of Medicine, New York, N.Y.). At day 7 of culture, the production of
HIV-1 p24 antigen indicated that RM replicated in CCR5-transfected
cells (p24 concentration, 1.9 ng/ml), whereas DK replicated in
CXCR4-transfected cells (>10 ng/ml). RM did not replicate in CXCR4
cells and DK did not replicate in CCR5 cells.
Combination experiments with AOP-RANTES and Met-SDF-1
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Combination of CCR5 and CXCR4 Inhibitors in Therapy of Human
Immunodeficiency Virus Type 1 Infection: In Vitro Studies of Mixed
Virus Infections
ABSTRACT
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(SDF-1), Met-SDF-1, and a modified form of RANTES,
aminooxypentane (AOP)-RANTES. The antiviral agents were
tested singly or in combination at 95 and 99% virus inhibitory
concentrations. Clinical R5 and X4 HIV-1 isolates were used.
AOP-RANTES inhibited R5 but not X4 viruses, whereas Met-SDF-1 had
the opposite effect. Combinations of these compounds inhibited mixed
infections with R5 and X4 viruses (95 to 99%), whereas single drugs
were less inhibitory (32 to 61%). Combinations of R5 and X4 inhibitors
are promising and deserve further evaluation.
TEXT
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(MIP-1), and MIP-1, belong
to the group of C-C chemokines that block HIV-1 entry into cells
(5).
, and MIP-1 (9, 12). The natural ligand for CXCR4
is stroma derived factor-1 (SDF-1), an -chemokine with chemotactic
properties for T lymphocytes and a developmental role in B lymphocyte
maturation (2, 25).
in
PBMC.
The inhibitory activities of aminooxypentane (AOP)-RANTES
and Met-SDF-1 were evaluated singly or in combination against
infections with a single HIV-1 isolate or a mixture of the two isolates
at a 50:50 ratio. Met-SDF-1 (lot no. 4488-208) was provided by
Genetics Institute (Cambridge, Mass.) and had the sequence MKPV at the amino terminus (35). AOP-RANTES was provided by Gryphon
Sciences, South San Francisco, Calif. (32). Susceptibilities
to Met-SDF-1 and AOP-RANTES were determined in
phytohemagglutinin-P-stimulated peripheral blood mononuclear
cells (PBMC) by using a fixed amount of infectious virus (1,000 50% tissue culture infective doses [TCID50s]) and a
multiplicity of infection of 0.01 TCID50/cell. Cell
cultures were either drug free (control wells) or pretreated with four
different Met-SDF-1 or AOP-RANTES concentrations in duplicate wells.
Met-SDF-1 was used at concentrations ranging from 0.35 to 2.80 µg/ml, and AOP-RANTES was used from 5 to 40 ng/ml. Antiviral effects
were tested at the 95 and 99% inhibitory concentrations
(IC95 and IC99) for each drug.
IC95s were 0.41 µg/ml for Met-SDF-1 and 38 ng/ml for
AOP-RANTES, whereas IC99s were 1.75 µg/ml for
Met-SDF-1 and 67.68 ng/ml for AOP-RANTES. Each combination
experiment was conducted once with compounds at their IC95s
and twice with compounds at their IC99s. HIV-1 inhibition
was achieved when a single viral isolate was targeted by its specific
single attachment inhibitor and when both antiviral agents were
combined for the treatment of infections by mixtures of the two
isolates, RM and DK (Table 1).
Suppression of individual viral replication was 75 to 99% during
combination experiments using the IC95 or IC99
of individual agents. In combination experiments using two inhibitors
against both viruses, the inhibition varied between 95 and 99%. When a
single agent was used in the presence of both X4 and R5 isolates, viral
inhibition was less effective (32 to 61% for AOP-RANTES and 45 to 49%
for Met-SDF-1).
TABLE 1.
Analysis of therapeutic combinations of AOP-RANTES and
Met-SDF-1 at IC95 and IC99 in PBMC
Passage of PBMC supernatant fluids onto CCR5- and CXCR4-transformed cells. The supernatant fluids from PBMC cultures infected with either DK or RM viruses with or without their inhibitors, as described above, were passaged in astroglioma U87MG-transformed CD4+ cells expressing either CXCR4 or CCR5, with 0.5 ml of culture supernatant fluids. Subcultures were maintained until day 7, and cytopathic effects were observed by day 4. Similar replication kinetics were observed for the two viruses in cells bearing the appropriate receptor. The expected patterns of virus inhibition by individual receptor inhibitors, or their combination, were observed, with the most complete inhibition of mixed infection of both cell types being observed when dual inhibitor IC99s had been used in PBMC. In that situation, viral cytopathic effects were not observed and HIV-1 p24 antigen production was minimal at day 7 (<0.1 to 3.1 ng/ml).
Analysis of the V3 region amino acid sequences of RM and DK. RM and DK viruses were amplified by a two-step PCR. The first step of the PCR was carried out with the primers PSA (5'-TACAATGTACACATGGAATT-3') and PSD (5'-ATTACAGTAGAAAAATTCC-3'), and the second step was carried out with the primers PSB (5'-TGGCAGTCTAGCAGAAGAAG-3') and PSC (5'-TCTGGGTCCCCTCCTGAGGA-5'). The V3 loop was sequenced using an ABI 377A automatic sequencer (Perkin-Elmer, Applied Biosystem Inc., Foster City, Calif.). The sequences were identified and analyzed by the Navigator and Factura DNA analysis software package (Perkin-Elmer). The results were compared to the sequences of the prototypic strains Ba-L, MN, and 89.6, with known macrophage-tropic, T-cell-tropic, and dually tropic phenotypes, respectively (6, 16, 17).
The RM virus had a sequence similar to the prototypic R5 strain Ba-L (identity for 27 of 35 amino acids), whereas the DK isolate resembled the prototypic X4 virus MN (identity for 22 of 35 amino acids). Data are shown in Fig. 1. Both viruses, RM and DK, had conserved regions in the central portion of the V3 domain, namely the GPGR region (15, 26), and were analogous to the other strains used in the comparison.
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was amplified, and V3 loops were sequenced. Figure 2 shows that in the absence of drug
pressure, RM viral sequences predominated. In the presence of
AOP-RANTES alone, DK sequences were exclusively observed, whereas when
Met-SDF-1 was used alone, RM sequences predominated. When both
drugs were used together, sequence mixtures were observed.
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Molecular clones derived from experiments in the presence of
AOP-RANTES and Met-SDF-1.
To delineate the role of individual
strains in mixed viral infections, PCR products corresponding to the V3
loop sequence were also cloned and single clones were sequenced. PCR
fragments of the V3 loop from proviral DNA were cloned in the pGEM-T
Easy Vector (Promega). JM109 cells were transformed with ligation
mixtures and plated onto Luria-Bertani agar with ampicillin
and 5-bromo-4-chloro-3-indoyl--D-galactopyranoside (X-Gal). Colonies
with the insert were reamplified with the primers PSB and PSC and were
used for DNA sequencing after PCR purification. The consensus sequence
derived from the single clones was identical to the corresponding
proviral sequence.
was used, we observed only RM virus
(10 of 10 clones).
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Need for new targets and combinations. Although current antiretroviral regimens have resulted in a dramatic reduction of HIV-1-associated mortality and morbidity, drug resistance is an emerging problem that will complicate these efforts (19). New and more potent regimens are needed, particularly those that target untapped HIV-1 replication sites. Chemokine receptors play important roles as coreceptors for HIV-1 entry into host cells (2, 14, 25). The discovery that chemokine receptors are coreceptors for HIV-1 has allowed the development of novel antiviral approaches, including specific chemokine-receptor antagonists (reviewed in references 3 and 27).
The process of HIV-1 attachment and entry involves several sequential steps involving gp120 binding to CD4 and the chemokine receptors CXCR4 or CCR5, followed by fusion of viral gp41 to the cell membrane. Early infection is often mediated by R5 viruses, and there is often an R5-to-X4 receptor shift during clinical deterioration to AIDS (7, 34). The archive of viruses carried by an HIV-1-infected individual may include both R5 and X4 viruses, suggesting that both cellular targets should be considered for strategic antiviral interventions. Among C-C chemokines, RANTES was demonstrated to use different cellular receptors, including CCR5 (18). Modification of the amino terminus of RANTES led to the identification of two compounds, Met-RANTES and AOP-RANTES, both of which exhibit a potent and selective receptor antagonism (28, 32). AOP-RANTES activity results in downregulation of the coreceptor due to the inhibition of recycling from the cytoplasm to the cell membrane (21). With regard to CXCR4 ligands, SDF-1 differs from SDF-1 in that SDF-1 lacks
the last four amino acid residues of the latter (2, 25, 30).
These molecules probably inhibit cell entry by X4 HIV-1 strains through
coreceptor competition. Some studies have focused on modified analogues
of SDF-1 as receptor antagonists and as inhibitors of viral entry
(22, 35).
Given the broad repertoire of viral isolates harbored by an infected
individual, single agents directed at a unique coreceptor may select
for virus with an alternative receptor tropism (13, 23; D. Schols, G. Bridger, G. Henson, and E. De Clercq,
Abstr. 7th Conf. Retroviruses Opportunistic Infect., abstr. S18, 2000). Hence, there is ample rationale for dual attack against both CXCR4 and
CCR5 receptors.
Our study demonstrates that both coreceptor blockers are necessary in
order to attain profound HIV-1 inhibition when viruses with mixed
tropism are present. We conducted experiments utilizing single or
combined drugs against infection with R5 or X4 viruses or against mixed
infection with these viruses. AOP-RANTES inhibited R5 but not X4
viruses, whereas Met-SDF-1 inhibited X4 but not R5 viruses. The
combination of AOP-RANTES and Met-SDF-1 inhibited dual infections
with R5 and X4 viruses (95 to 99%), whereas single drugs suppressed
dual infections less well (32 to 61%). Sequencing and cloning studies
showed the presence of both viral genomes in supernatant fluids from
mixed virus cultures in the absence of drug pressure. In the presence
of specific inhibitors, viruses with alternative tropisms were cloned
and sequenced from culture supernatant fluids.
Our observations establish the proof of principle for a dual-receptor
attack against HIV-1 in vitro and suggest the future clinical
development of such a strategy. However, it is only through carefully
designed and conducted therapeutic trials that the clinical validity of
these in vitro studies can be determined. The potential pharmacological
problems with this class of compounds, as well as their possible
systemic toxicities, must also be considered in further clinical development.
Although our study utilized specific peptide antagonists of chemokine
receptors, there is a need for the development of small-molecule, orally bioavailable inhibitors directed against either X4 or R5 viruses. Some of these have already been developed (1, 10, 11, 24;
B. M. Baroudy, Abstr. 7th Conf. Retroviruses Opportunistic Infect., abstr. S17, 2000). One recent report (C. Tremblay, C. Kollman,
F. Giguel, T. C. Chou, and M. S. Hirsch, Abstr. 7th Conf. Retroviruses Opportunistic Infect., abstr. 500, 2000) described strong
antiviral synergy between one small X4-inhibitory molecule, AMD3100
(10), and the gp41-specific inhibitor T-20 (20),
providing further support for the concept of combination therapy
targeting HIV-1 attachment and entry.
Nucleotide sequence accession numbers. The V3 loop sequences identified in this study were submitted to GenBank and assigned accession numbers AF234190 through AF234233, AF234234 (RM), and AF234235 (DK).
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ACKNOWLEDGMENTS |
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We thank Bianca M. Ghisi for editorial assistance and Elizabeth L. Kaplan for continuous support.
We acknowledge the financial support of Progetto Terapia Antiretrovirale, Istituto Superiore di Sanità (Rome, Italy), grant 1997 no. 30A.0.43, and NIH grant CA 12464. S.R. was supported by a NATO-CNR senior fellowship (218.1861).
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FOOTNOTES |
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* Corresponding author. Mailing address: Istituto di Malattie Infettive e Tropicali, Università di Milano, Ospedale Luigi Sacco, via GB Grassi 74,20157 Milan, Italy. Phone: 39.02.39042676. Fax: 39.02.3560805. E-mail: rusconi{at}mailserver.unimi.it.
This paper is dedicated to the memory of Alessandro Caporali.
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Journal of Virology, October 2000, p. 9328-9332, Vol. 74, No. 19
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Nakata, H., Steinberg, S. M., Koh, Y., Maeda, K., Takaoka, Y., Tamamura, H., Fujii, N., Mitsuya, H.
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