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Journal of Virology, May 2001, p. 4402-4406, Vol. 75, No. 9
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.9.4402-4406.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The LD78beta Isoform of MIP-1alpha Is the Most Potent CC-Chemokine in Inhibiting CCR5-Dependent Human Immunodeficiency Virus Type 1 Replication in Human Macrophages

Stefano Aquaro,1,* Patricia Menten,2 Sofie Struyf,2 Paul Proost,2 Jo Van Damme,2 Erik De Clercq,1 and Dominique Schols1

Laboratory of Experimental Chemotherapy1 and Laboratory of Molecular Immunology,2 Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

Received 14 September 2000/Accepted 29 January 2001


    ABSTRACT
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The CC-chemokines RANTES, macrophage inflammatory protein 1alpha (MIP-1alpha ), and MIP-1beta are natural ligands for the CC-chemokine receptor CCR5. MIP-1alpha , also known as LD78alpha , has an isoform, LD78beta , which was identified as the product of a nonallelic gene. The two isoforms differ in only 3 amino acids. LD78beta was recently reported to be a much more potent CCR5 agonist than LD78alpha and RANTES in inducing intracellular Ca2+ signaling and chemotaxis. CCR5 is expressed by human monocytes/macrophages (M/M) and represents an important coreceptor for macrophage-tropic, CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) strains to infect the cells. We compared the antiviral activities of LD78beta and the other CC-chemokines in M/M. LD78beta at 100 ng/ml almost completely blocked HIV-1 replication, while at the same concentration LD78alpha had only weak antiviral activity. Moreover, when HIV-1 infection in M/M was monitored by a flow cytometric analysis using p24 antigen intracellular staining, LD78beta proved to be the most antivirally active of the chemokines. RANTES, once described as the most potent chemokine in inhibiting R5 HIV-1 infection, was found to be considerably less active than LD78beta . LD78beta strongly downregulated CCR5 expression in M/M, thereby explaining its potent antiviral activity.


    TEXT
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Macrophage inflammatory protein 1alpha (MIP-1alpha ) exists in two nonallelic isoforms, LD78alpha and LD78beta , with high-level sequence homology. The secreted proteins differ in only 3 amino acids: the penultimate NH2-terminal residue and amino acids 39 and 47 (10, 21, 23). The biological relevance, also in terms of antiviral activity, of the NH2-terminal residues of CXC- and CC-chemokines has been convincingly demonstrated (26, 27, 29, 31-33, 42). Besides MIP-1alpha , the CC-chemokines RANTES and MIP-1beta are natural ligands for the CC-chemokine receptor CCR5 and are inhibitors of macrophage-tropic (M-tropic) human immunodeficiency virus (HIV) strains (7).

LD78beta was reported to be much more potent than LD78alpha and RANTES in inducing intracellular Ca2+ signaling and chemotaxis preferentially through the CC-chemokine receptor CCR5 (20, 22, 43). In these studies, the anti-HIV activity of LD78beta in peripheral blood mononuclear cells (PBMCs) was investigated (20), however, its activity in human monocytes/macrophages (M/M) had not been determined.

The chemokine receptor CCR5 is expressed by M/M and represents the most important coreceptor for M-tropic R5 HIV type 1 (HIV-1) strains to enter the cells (1, 13, 14, 34, 36, 39-41). Macrophages may play an important role in all phases of HIV infection. Infected macrophages are present in all body tissues of HIV patients (12, 17-19) and represent the most important cellular reservoir for the virus during antiviral therapy (4, 24, 30). In fact, M/M secreting nerve growth factor survive after HIV infection (9) and produce high and stable levels of virus for a long period of time (S. Aquaro, T. Guenci, P. Bagnarelli, M. Clementi, A, Modesti, R. Caliò, and C. F. Perno, 4th Intl. Workshop HIV, Cells of Macrophages Lineage, and Other Reservoirs, p. 29, 1999). In the central nervous system, more then 90% of the HIV-1-infected cells are M/M (8, 12, 15, 37), and CCR5 Delta 32 heterozygosity prevents the development of the AIDS dementia complex (38). At the same time, the downregulation of CCR5 expression by CC-chemokines in macrophages is correlated with a reduction of virus entry and replication (11). These data demonstrate the relevance of CCR5 and thus the important role of CC-chemokines in reducing HIV entry and hence virus replication through their interaction with CCR5. Here, we have studied the antiviral efficacy of LD78beta , in comparison with those of LD78alpha and the other CCR5-interacting CC-chemokines, RANTES and MIP-1beta , in purified macrophages. To evaluate the antiviral activities of LD78alpha and LD78beta , M/M were incubated with the chemokines for 20 min at different concentrations and then infected by the R5 HIV-1BaL strain. LD78beta showed a potent dose-dependent inhibition and antiviral activity against HIV-1BaL. As shown in Fig. 1, at an LD78beta concentration of 100 ng/ml, viral p24 antigen (Ag) production dropped from 40,300 pg/ml to 2,070 pg/ml (94% inhibition). In contrast, LD78alpha only weakly inhibited viral replication at a concentration of 100 ng/ml (roughly 20% inhibition) (Fig. 1). Thus, the antiviral activity of LD78beta in M/M was far superior to that of LD78alpha .


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  		FIG. 1.   Dose-dependent antiviral activity of LD78beta in HIV-1-infected M/M. Macrophages were obtained from the blood of healthy HIV-seronegative donors by previously published procedures (25). Briefly, PBMCs were separated by Ficoll-Hypaque gradient centrifugation and seeded in plastic 48-well plates (Costar, Cambridge, Mass.) at a density of 1.8 × 106 cells/ml in RPMI 1640 (Gibco, Gaithersburg, Md.) supplemented with 50 U of penicillin/ml, 50 µg of streptomycin/ml, 2 mM L-glutamine, and 20% heat-inactivated, mycoplasma- and endotoxin-free fetal calf serum (HyClone, Logan, Utah) (complete medium). On the 5th day of culture, nonadherent cells were removed by repeated gentle washing with warm complete medium. Adherent cells obtained with this technique consisted of >95% differentiated M/M. After purification, M/M were cultured in a humidified chamber with 5% CO2 at 37°C in the presence of the same medium. Further details are described elsewhere (25). Macrophages were exposed to various concentrations of CC-chemokine LD78beta () or LD78alpha () for 20 min; then they were challenged with HIV-1BaL at 300 50% cell culture infective doses per ml. After 2 h of incubation, M/M were extensively washed with warm complete medium to remove the excess virus and then cultured in the presence of chemokines under the conditions used previously. M/M were washed and fed every 5 days with fresh medium and replenished with chemokines. Supernatants were collected at day 12 after virus challenge, and virus production was determined by Ag capture assay with a commercially available p24 Ag kit (NEN Life Science Products Inc., Boston, Mass.). Human recombinant MIP-1alpha isoform LD78alpha was purchased from PeproTech Inc. (Rocky Hill, N.J.). The 7.793-kDa LD78beta was synthesized by 9-fluorenylmethoxycarbonyl (fMOC) solid-phase peptide synthesis (20). Data represent the means of values from two independent experiments, each run in triplicate. Error bars show the standard deviations.

The antiviral activities of LD78alpha and LD78beta were also evaluated by intracellular p24 Ag staining to determine the percentage of HIV-1-infected M/M. As can be seen in Fig. 2, 42% of the cells from HIV-infected M/M cultures stained positive for p24 Ag, whereas the level decreased to about 11% in the LD78beta -treated cells (at 100 ng/ml). In contrast, no difference in numbers of p24 Ag-positive cells was observed between the untreated HIV-infected and LD78alpha -treated HIV-infected cells (Fig. 2).


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  		FIG. 2.   Intracellular p24 Ag detection in M/M. At day 14 after infection, M/M were carefully washed with cold phosphate-buffered saline to remove excess virus and were detached by using 1 mM EDTA for 5 min followed by gentle scraping. The percentage of HIV-infected M/M was determined by intracellular staining for p24 Ag, using the fluorescein isothiocyanate (FITC)-conjugated anti-p24 mAb KC-57-FITC (Coulter, Hialeah, Fla.). Cells were analyzed by using a FACScan flow cytometer (Becton Dickinson, San Jose, Calif.). At a concentration of 100 mg of LD78beta /ml, viral p24 Ag expression was strongly inhibited (D), whereas at the same concentration, LD78alpha showed no antiviral activity (C). (B) HIV-1BaL-infected M/M; (A) mock-infected M/M. The results of one representative experiment of three independent experiments are shown.

To compare the anti-HIV efficacy of LD78beta with those of the other CCR5-binding chemokines, RANTES and MIP-1beta , additional experiments were performed in M/M. The MIP-1alpha isoform LD78beta exhibited the highest antiviral activity against HIV-1BaL. RANTES reached 92% inhibition of HIV replication at a concentration of 500 ng/ml, while LD78beta suppressed HIV replication by 93% at 100 ng/ml (i.e., at a fivefold-lower concentration than RANTES); moreover, MIP-1beta , considered the most specific CCR5 ligand, inhibited virus replication by about 30% at 500 ng/ml (data not shown). Therefore, as shown in Table 1, the 50% effective concentration (EC50) of LD78beta against HIV-1BaL in M/M was 21 ng/ml, which is 16-fold lower than that of LD78alpha (EC50, 351 ng/ml). Also, a more than 10-fold difference in the EC90s of LD78alpha and LD78beta was observed (Table 1). RANTES, with an EC50 and an EC90 of 149 and 478 ng/ml, respectively (Table 1), was six- to sevenfold less active than LD78beta . With an EC50 of almost 1,000 ng/ml (Table 1), MIP-1beta was found to be the least potent chemokine in inhibiting viral replication.

                              
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  		TABLE 1.   Antiviral activity of LD78beta , LD78alpha , RANTES, and MIP-1beta against HIV-1BaL strain and a clinical R5 HIV-1 isolate in macrophagesa

To confirm that LD78beta has potent antiviral activity against M-tropic HIV strains, and not only against the cell culture-adapted virus strain HIV-1BaL, we performed additional experiments with primary R5 HIV-1 clinical isolate (HIV-1 isolate 15). This virus isolate was obtained after only one passage in PBMCs and replicated in U87.CD4.CCR5-transfected cells but not in U87.CD4.CXCR4 cells, confirming its CCR5 usage (data not shown). Here, again, the chemokine LD78beta was the most active in inhibiting viral replication, with an EC50 of 28 ng/ml (Table 1). The other chemokines were somewhat more active against this clinical viral isolate than against HIV-1BaL (Table 1).

We demonstrated previously that the antiviral activity of a compound that inhibits virus entry in fresh monocytes (such as the sulfated polysaccharide dextran sulfate or the bicyclam AMD3100) is different from that in macrophages (3). Therefore, we also assessed the anti-HIV efficacy of LD78beta in freshly isolated monocytes. At a concentration of 100 ng/ml, LD78beta inhibited HIV replication by 85% (EC50, 35 ng/ml). In sharp contrast, at a concentration of 100 ng/ml, RANTES had no antiviral activity in fresh monocytes (data not shown). It has been previously reported that RANTES has no or only weak activity against HIV-1 in freshly isolated monocytes (28, 31). A likely explanation for this phenomenon is that only the NH2-terminally truncated form of RANTES has anti-HIV activity and that monocytes express very low, or undetectable, levels of CD26/dipeptidyl peptidase IV, which is responsible for NH2-terminal truncation of RANTES (29).

Because previous studies demonstrated that downregulation of HIV coreceptors by their natural ligands contribute to the inhibition of viral replication (2, 16), we examined the efficiency of LD78beta at downregulating CCR5. As shown in Fig. 3, expression of CCR5 from the surface of monocytes is shown for LD78beta , in comparison with LD78alpha and MIP-1beta . LD78beta was much more effective (after 1 h of incubation at 37°C) than LD78alpha or MIP-1beta at downregulating CCR5; it showed a marked downregulation at 40 ng/ml, whereas for LD78alpha and MIP-1beta a weak effect was observed only at a concentration of 200 ng/ml. This enhanced potency of LD78beta in receptor binding and downregulation may explain its potent anti-HIV activity and is probably due to its greater affinity for CCR5 (20).


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  		FIG. 3.   Downregulation of CCR5 from the surfaces of monocytes by LD78beta , LD78alpha , and MIP-1beta . PBMCs were suspended in complete medium and seeded in petri dishes at a concentration of 1.5 × 106 cells/cm2. After 2 h of incubation, all nonadherent cells were removed by gentle washing with warm medium. Adherent cells were scraped from the plates, counted, and suspended in complete medium at a concentration of 2 × 105 ml. After this purification step, more then 97% of the cells were monocytes, as determined by CD14 staining. Monocytes were incubated with LD78beta (40 ng/ml) (B), LD78alpha (200 ng/ml) (C), or MIP-1beta (200 ng/ml) (D) for 1 h at 37°C. In panel A, the cells were incubated with medium alone. Surface CCR5 was detected with CCR5 monoclonal antibody clone 2D7 (PharMingen, San Diego, Calif.) and analyzed by flow cytometry.

This study shows that the MIP-1alpha isoform LD78beta is the most potent CC-chemokine described so far in terms of inhibiting R5 HIV-1 infection of macrophages and monocytes. The inhibitory effect of LD78beta on viral replication may be ascribed to its high affinity for CCR5 and the subsequent downregulation of this coreceptor. The potent anti-HIV-1 activity of LD78beta compared with that of LD78alpha is conferred by differences in only 3 amino acids (20), with the NH2-terminal dipeptide of LD78alpha seemingly important for receptor affinity (33).

Our findings that RANTES and MIP-1alpha /LD78alpha have EC50s of about 60 and 120 ng/ml, respectively, are in agreement with previously published data (35). The previously reported order for the anti-HIV activities of the CC-chemokines in M/M, RANTES > MIP-1beta  > MIP-1alpha /LD78alpha (5), should be changed to the following order: MIP-1alpha /LD78beta  > RANTES > MIP-1alpha /LD78alpha  > MIP-1beta . Further experiments are required to determine if MIP-1alpha /LD78alpha is consistently more potent than MIP-1beta in inhibiting HIV-1 replication in M/M. The superior anti-HIV-1 activity of LD78beta has to be interpreted in the light of the isolation from cultured T cells of MIP-1alpha , MIP-1beta , and RANTES as suppressors of HIV-1 infection (7). Increased production of the CC-chemokines MIP-1alpha , MIP-1beta , and RANTES in repeatedly HIV-1-exposed subjects is correlated with protection against HIV-1 infection; MIP-1alpha appears sooner and attains higher concentrations than MIP-1beta and RANTES (6, 44). These clinical data on natural resistance to HIV-1 infection, not linked to a deletion mutation in the CCR5 gene, are in agreement with the higher antiviral potency of the LD78beta isoform of MIP-1alpha , as previously shown in PBMCs (20, 22) and here confirmed for M/M.


    ACKNOWLEDGMENTS

We thank Sandra Claes and Erik Fonteyn for excellent technical assistance.

This work was supported by grants from the Fonds voor Wetenschappelijk Onderzoek (FWO)---Vlaanderen (Krediet no. G.0104.98) and the Geconcerteerde Onderzoeksacties (Vlaamse Gemeenschap) (Krediet no. 00/12). S.A. was supported by a grant from Istituto Superiore di Sanità, Rome, Italy.


    FOOTNOTES

* Corresponding author. Mailing address: Department of Experimental Medicine, University of Rome "Tor Vergata," Rome, Italy. Phone: 39 06 7259 6553. Fax: 39 06 72596552. E-mail: aquaro{at}uniroma2.it.


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Journal of Virology, May 2001, p. 4402-4406, Vol. 75, No. 9
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.9.4402-4406.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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