, and MCP-3, and enhancement by MCP-1
* AIDS Immunopathogenesis Unit, and
Division of Infectious Diseases, San Raffaele Scientific Institute, Milan;
Institute for Scientific Interchange Foundation, Torms, Italy;
Department of Immunology and Cell Biology, "Mario Negri" Institute for Pharmacological Research, Milan; and
Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy
Correspondence: Dr. Guido Poli, P2/P3 Laboratories, DIBIT, Via Olgettina no. 58, 20132, Milano, Italy. E-mail: poli.guido{at}hsr.it
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(MIP-1), monocyte
chemotactic protein-1 (MCP-1), and MCP-3 on virus replication in
cultures established from CD8+ T cell-depleted peripheral
blood mononuclear cells (PBMC) of HIV-infected individuals that were
either cocultivated with allogeneic T cell blasts (ATCB) of uninfected
individuals or directly stimulated by mitogen plus interleukin-2.
RANTES was the only chemokine that showed a clear-cut suppressive
effect on HIV replication in both culture systems, although inhibitory
effects were frequently also observed with MIP-1, MCP-3, and,
occasionally, with MCP-1. In contrast, MCP-1 frequently enhanced HIV
production in most patients’ cultures or cocultures that were
characterized by secreting relatively low levels (<20 ng/mL) of MCP-1.
When CD8-depleted PBMC of HIV+ individuals were
cocultivated with ATCB of uninfected healthy donors, a positive
correlation was observed between MCP-1 concentrations and the
enhancement of HIV-1 replication occurring after depletion of
CD8+ cells from donors’ cells. Depletion of
CD14+ cells (monocytes) from ATCB resulted in the
down-regulation of virus replication during co-cultivation with
CD8-depleted PBMC of infected individuals. Of interest, MCP-1
up-regulated HIV production in these CD14-depleted ATCB cocultures.
Altogether these observations suggest that MCP-1 may represent an
important factor enhancing HIV spreading, particularly in anatomical
sites, such as the brain, where infection of macrophages and microglial
cells plays a dominant role.
Key Words: patients • CD8 • CD14
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(MIP-1), and MIP-1ß, were identified as major
HIV-suppressive factors secreted by activated CD8+ T cells
of HIV-infected individuals and CD8+ T cell lines
[2
]. Elevated and sustained secretion of these three CC
chemokines from CD4+ peripheral blood mononuclear cells
(PBMC) of exposed uninfected individuals was responsible for their
resistance to in vitro infection by non-syncytium-inducing
(NSI) HIV strains [3
]. Unlike anti-inflammatory
cytokines and interferons (IFNs), which can suppress transcriptional
and posttranscriptional steps in the HIV life cycle [1
],
CC chemokines act via binding to promiscuous seven-transmembrane-domain
receptors on the cell surface serving as viral entry co-receptors
together with CD4 [4
, 5
]. Conversely, CXCR4
has been shown to act as co-receptor for fusogenic (SI) viruses, which
typically emerge during late-stage HIV infection [6
];
its natural ligand, the CXC chemokine stromal cell-derived factor-1
(SDF-1), exerts selective inhibitory effect on the replication of this
class of HIVs [7
8
9
]. Although the above-mentioned studies are very consistent in defining the mechanism of action of chemokines in blocking viral entry, little information is available on the role of this family of pro-inflammatory molecules in controlling HIV replication in naturally infected cells, i.e. cells obtained from either HIV-infected [10 , 11 ] or exposed uninfected [12 ] individuals. In this regard, PBMC depleted of the CD8+ cellular fraction (which is known to exert a potent suppressive effect on HIV expression via release of soluble factors, including CC chemokines [11 , 13 , 14 ]) can be efficiently manipulated ex vivo in order to study HIV replication even in the absence of allogeneic T cell blasts [15 ]. Therefore, we have investigated the role of individual CC chemokines on HIV replication in CD8-depleted PBMC obtained from HIV-infected individuals. Patients’ cells were either directly stimulated by mitogen and interleukin-2 (IL-2), or were cocultivated with allogeneic T cell blasts from uninfected individuals (i.e., following a standard protocol to obtain primary viral isolates). Our results support an important role of CC chemokines, and of RANTES in particular, as potent inhibitors of virus production, but also indicate that MCP-1 is likely an up-regulator of HIV replication.
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View this table: [in a new window] |
Table 1. HIV-Infected Individuals
|
Ex vivo HIV replication in CD8-depleted PBMC of
HIV-infected individuals
CD8-depleted PBMC of HIV-infected individuals were resuspended
in complete medium plus IL-2 (10 U/mL; Boehringer, Mannheim, Germany),
and stimulated with 5 µg/mL PHA-P (Sigma Chemical, St. Louis, MO;
direct cultures), or cocultivated with 3 day-old PHA-stimulated PBMC
(allogeneic T cell blasts, ATCB) obtained from HIV-seronegative
individuals at a ratio of 1 patients’ CD4+ PBMC per 2
ATCB, respectively (cocultures). Both cultures and cocultures were
seeded in 96- or 48-well plates (Falcon, Becton Dickinson Labware,
Lincoln Park, NJ) at the initial concentrations of 2.5 x
105 cells/mL/well (direct cultures) and 7.5 x
105 cells/mL/well (cocultures), respectively, in duplicate
or triplicate wells/condition. Individual chemokines were added to
cultures and cocultures of CD8-depleted PBMC simultaneously with PHA
plus IL-2 or ATCB, respectively, at the fixed concentration of 100
ng/mL. This concentration of RANTES was previously observed to induce a
potent (>90%) suppressive effect on the replication of several
primary HIV isolates in T cell blasts [E. Vicenzi, unpublished
results]. Furthermore, these chemokine concentrations are in the range
used by other investigators in different models of in vitro
infection. Individual chemokines were added to the cultures a second
time after 3 days.
Supernatants were collected every 2–3 days for 2–4 weeks, and complete medium enriched of IL-2 was added to cultures and cocultures. Supernatants were stored at -80°C until tested for Mg2+-dependent RT activity content [18 ] or HIV-1 p24 Gag-antigen (Ag) by a commercially available enzyme-linked immunosorbent assay (ELISA; Coulter).
All recombinant chemokines were purchased from R & D Systems (Minneapolis, MN). MCP-1 concentrations in culture supernatants were determined by ELISA using the 5D3-F7 mAb as first Ab for plate coating, as described [19 , 20 ].
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also
showed potent suppressive effects on virus expression (Fig. 1C
and 1D)
. Unlike RANTES, modest (Fig. 1B
and 1F)
to strong (Fig. 1A)
enhancement as well as no appreciable effects (Fig. 1E)
on virus
replication were also observed after addition of MIP-1. Inhibition
(Fig. 1C 1D
and 1F)
but also enhancement (Fig. 2
) was observed with MCP-3, a CC chemokine that shares binding to
CCR-1 and CCR3 with RANTES, and that was previously found either
ineffective [21
] or inhibitory [22
] in
in vitro infected cells. In sharp contrast, MCP-1, a
prototypical CC chemokine that was previously described as not
influential during in vitro infection [2
],
frequently enhanced HIV replication in several cultures and cocultures
established from infected individuals compared to parallel untreated
conditions or to cultures that were supplemented with RANTES (Fig. 1A
1B 1D
and 1E)
. Inhibitory effects (range 20–90%) were also observed
with MCP-1, although they were usually less potent than those obtained
by RANTES in parallel patients’ cell cultures (Fig. 1C
and 1F)
. A
summary of the effects exerted by CC chemokines in the different
cultures and cocultures of CD4+ PBMC of infected
individuals is represented in Figure 2
, which shows the modulatory
effects exerted by individual chemokines at the peak levels of virus
replication compared with parallel untreated cultures. MCP-1 and RANTES
showed the most extreme regulatory patterns, in that the former caused
enhancement (
2-fold HIV replication over control cell cultures) in
six out of ten and five out of nine individual cultures and cocultures,
respectively. Either no effect or inhibition of virus production by
MCP-1 was seen in cell cultures or cocultures of five patients (Fig. 2) . Of note is the fact that RANTES had a consistent suppressive effect
in all but 1 cell culture and coculture from infected individuals (Fig. 2)
. Intermediate patterns were seen with MIP-1 and MCP-3, although
an inhibitory pattern was their most frequent effect on virus
replication in patients’ CD8-depleted PBMC (Fig. 2)
.
 View larger version (26K): [in a new window] |
Figure 1. HIV replication in direct cultures and cocultures of CD8-depleted PBMC
of infected individuals. Regulatory effects of different CC chemokines.
A potent suppressive effect was observed in all patients’ cultures and
cocultures in the presence of RANTES, including those established from
patient CSL-6 harboring a SI virus. Suppression, but also enhancement
or lack of effect was seen with other chemokines, particularly with
MCP-1.
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 View larger version (16K): [in a new window] |
Figure 2. Summary of the regulatory effects of different CC chemokines on HIV
replication in direct cultures (dc; open symbols) or cocultures (cc;
filled symbols) of CD8-depleted PBMC of infected individuals. Results
are expressed as ratios of peak levels of HIV replication of
chemokine-treated cell cultures over those of parallel cultures
maintained in the absence of chemokines. Effects similar to those
reported here for MIP-1 was observed in a minority of patients’
cell cultures incubated with MIP-1ß. RANTES inhibitory effect was
more potent in cc than in dc (P = 0.05).
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Endogenous MCP-1 and regulatory effects of recombinant MCP-1 on HIV
replication
Sustained secretion of RANTES, MIP-1, and MIP-1ß from
CD4+ PBMC of exposed uninfected individuals has been
correlated with a state of in vitro resistance from
infection by NSI HIV [3
, 23
]. These
findings demonstrate that autocrine/paracrine secretion of certain
chemokines can profoundly affect HIV replication, as previously
observed with other cytokines [reviewed in ref. 1 ]. We therefore
investigated whether secretion of RANTES or MCP-1 (which showed the two
most divergent effects on virus replication when exogenously added to
patients’ CD8-depleted PBMC) may have played a role in HIV replication
in untreated cultures and/or have potentially influenced the response
to individual chemokines. No substantial differences were observed in
terms of RANTES concentrations detectable after 3 and 6 days (ranging
between 1 and 5 ng/mL; data not shown) in untreated CD8-depleted PBMC
cultures. In contrast, when the potential effect of exogenous MCP-1 was
investigated in patients’ CD8-depleted cultures, enhancement was
observed exclusively when the control, chemokine-untreated cell
cultures secreted relatively low levels (
20 ng/mL) of this chemokine,
whereas no regulatory effects and even inhibition by exogenously added
MCP-1 occurred in cultures characterized by a higher endogenous
secretion of the chemokine (P = 0.003, Spearman;
Fig. 3
). Furthermore, a strong correlation was observed between the
extent of the enhancement of HIV replication caused by the removal of
the CD8+ cellular fraction from normal donors’ PBMC and
the levels of MCP-1 produced during coculture (P =
0.0001, r = 0.979). A less stringent correlation was
also observed between endogenous MCP-1 secretion and HIV enhancement
caused by the depletion of CD16+ cells of normal donors
(P = 0.093, r = 0.74; data not shown).
 View larger version (17K): [in a new window] |
Figure 3. Correlation between endogenous MCP-1 secretion and enhancement of HIV
replication by recombinant MCP-1 in cultures of CD8-depleted PBMC of
infected individuals. Y-axis: effect of recombinant MCP-1
(100 ng/mL) on HIV replication. The values indicate fold induction or
suppression vs. untreated parallel cultures at the peak of viral
replication. X-axis: concentrations of endogenous MCP-1 in
supernatants of CD8-depleted PBMC cultures of HIV+
individuals after 72 h. Detectable, but lower levels of MCP-1 were
observed in supernatants of the same cultures collected after 6 days of
cultivation. Enhancement of viral replication was associated with
concentrations of endogenous MCP-1 lower than 20 ng/mL (tested in
parallel chemokine-untreated cultures), whereas no effect or inhibition
of HIV spreading were seen when the levels of endogenous MCP-1 in
parallel control cultures were above 20 ng/mL (Spearman
r = 0.76, 95% CI: -0.34 to -0.92, P =
0.0025).
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 View larger version (18K): [in a new window] |
Figure 4. MCP-1 enhances HIV replication in cocultures of CD8-depleted PBMC from
infected individuals and CD14-depleted ATCB. Depletion of
CD14+ cells (mostly monocytes) from ATCB shuts off virus
replication, as reported [17
], whereas MCP-1 restores
HIV production to levels comparable to those observed during
cocultivation of CD8-depleted PBMC of infected individuals with
unfractionated ATCB.
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and MCP-3 showed a predominant
inhibitory effect on virus replication. In contrast, MCP-1 frequently
enhanced HIV replication in patients’ cultures and cocultures. Chemokine receptors act as co-factors of HIV infection of CD4+ T lymphocytes and macrophages by mediating HIV entry [reviewed in refs. 4 and 5]. CCR-5 is clearly the predominant co-receptor for most CCR5-dependent/NSI strains, recently renamed R5 viruses [24 ], whereas CXCR4 is the predominant co-receptor of SI/X4 viruses, although its use is frequently in addition to rather than substitutive of CCR5 [25 , 26 ]. Taken together, these results support a general model in which different HIV strains may utilize different CCRs for gaining access to CD4+ target cells.
The possibility that HIV may use different co-receptors for entry coupled with the fact that the virus exists in the body as a mixture of quasi-species, may provide a potential explanation of the different modulatory effects observed in our study by using different CC chemokines. In particular, we have investigated the ability of the virus to spread in CD4+ cells obtained from infected individuals in the presence or absence of exogenously added chemokines. CD8+ cells include an important fraction of T lymphocytes and most natural killer cells, both cell types characterized by cytolytic potential and by the capacity of releasing HIV-suppressive CC chemokines and other antiviral soluble factors [2 , 14 , 15 , 17 , 27 ]. Therefore, removal of CD8+ cells was necessary in order to obtain viral replication ex vivo as well as to study the contribution of individual chemokines to HIV spreading. Our results fully support previous conclusions on the suppressive effect of certain CC chemokines, and of RANTES in particular, on CD4+ cells infected in vitro with HIV-1.
MCP-3, which shares the ability to bind different CCRs with other chemokines, including RANTES (binding to CCR-1 and CCR-3), and MCP-1 (ligand of CCR-2A and CCR-2B), suppressed virus replication in most patients’ cell cultures, although lack of effect and occasional enhancement was also observed (Figs. 1 and 2) . Of note is the fact that eotaxin, which exclusively binds to CCR-3, also inhibited HIV entry and replication [28 , 29 ] and that inhibitory effects of MCP-3 have been previously observed during in vitro HIV infection [22 ]. Thus, our observation that MCP-3 can suppress HIV replication can be interpreted in support of a physiological role for CCR-3 in viral spreading in vivo.
MCP-1 has also shown a complex spectrum of effects in primary
CD4+ PBMC of infected individuals, although enhancement of
HIV replication was the predominant pattern observed. These effects
were not associated with obvious toxicity (distinguishable from
HIV-induced cell death or syncytia formation in the case of cells from
patient CSL-6) or substantial differences in cell proliferation.
MCP-1-mediated enhancement of HIV replication was observed in five out
of nine direct cultures established from different infected
individuals. Furthermore, exogenous MCP-1 increased virus replication
in CD8-depleted cell cultures characterized by a relatively poor
secretion of endogenous MCP-1 (20 ng/mL), whereas lack of effect and
even inhibition of viral replication were seen when higher
concentrations of endogenous MCP-1 were released in supernatants of
chemokine-untreated parallel cell cultures. These results suggest that
MCP-1 may act in an autocrine/paracrine fashion in regulating HIV
replication, as previously described for other pro-inflammatory
cytokines, including tumor necrosis factor , IL-1ß, IL-6, and
interferon-
[30
31
32
33
]. This hypothesis is supported by
the observation that a strong correlation was observed between the
levels of secreted MCP-1 and the enhancement of HIV replication
observed in cocultures of patients’ cells and ATCB that have been
depleted of the CD8+ cell fraction.
Monocytes are an important source of MCP-1 and we had previously reported that their depletion from ATCB caused a profound down-regulation of virus replication during co-cultivation with CD8-depleted PBMC of infected individuals (likely as a result of predominance of CD8+ and CD16+ inhibitory effects) [17 ]. Of interest, we observed that MCP-1 could functionally "replace" CD14+ cells in their enhancing role on HIV replication, at least in some donors.
Chemokine-mediated enhancement by either MCP-1 or RANTES has been previously reported and correlated to either presence and emergence of SI viruses in infected PBMC of seropositive individuals [11 ] or during in vitro infection of monocyte-derived macrophages (MDM) [34 ] or PBMC from some, but not all seronegative donors [35 , 36 ]. Unlike inhibition of HIV infection, chemokine-mediated enhancement of virus replication was found to be dependent on signaling from the chemokine receptor(s), in that it was abolished by pertussis toxin [11 ], a well-known inhibitor of G-protein-mediated intracellular events [37 ]. It should be underscored, however, that both pertussis toxin and its B-oligomeric subunits have been recently demonstrated to possess potent HIV-inhibitory activity, which, in the case of R5 viruses occurred at the entry level in a chemokine-like fashion [38 ]. These recent acquisitions shed new light on the interpretation that chemokine interference with viral entry does not require signaling.
Our findings of suppressive effects on HIV replication mediated by individual chemokines, particularly RANTES, confirm the importance of these molecules as potential physiological or pharmacological agents against HIV infection and spreading. The mechanism of action of CC chemokines in patients’ cultures appears more complex than predictable from the previous findings in in vitro models of infection. If chemokine co-receptor blockade can explain the suppressive effects observed in patients’ cells, no simple explanations can be formulated for the enhancing effects consistently observed with MCP-1 and occasionally seen with other chemokines except RANTES. Of interest, MCP-1 and MCP-3 share CCR-2 as cell-surface receptor, although their global effects on HIV replication from patients’ PBMC was substantially different. This observation suggests that other CCR (i.e. CCR-1 and/or CCR-3) mediate the suppressive effects of MCP-3, as previously described for in vitro infection also in the case of eotaxin, which exclusively binds to CCR3 [28 , 29 ]. On the other hand, CCR-2 can be used as viral co-receptor for entry, as in the case of the multitropic virus 89.6 [39 , 40 ], whereas anti-CCR2 mAb have been reported to inhibit viral replication [41 ]. This latter study is consistent with a potential autocrine/paracrine role of MCP-1 sustaining HIV replication. However, a number of alternative hypotheses can be formulated to explain the inductive effects of certain CC chemokines, including the triggering of specific signal transduction pathways, receptor phosphorylation, homologous and heterologous receptor desensitization, as also discussed in other studies [38 , 41 42 43 ].
Concerning the role of chemokine levels in HIV-infected individuals, we
have previously failed to observe an increased production of several CC
chemokines, including MIP-1, MIP-1ß, and MCP-1 in the plasma of
individuals at different stages of infection, including long-term
non-progressors [44
], whereas relatively high levels of
RANTES (10–30 ng/mL) were detected in plasma, likely as a consequence
of platelet activation after blood draw [E. Vicenzi et al.,
unpublished observations]. In contrast, we and others have observed a
selective increased accumulation of MCP-1 in the cerebrospinal fluid of
AIDS patients with cytomegalovirus and/or HIV-induced encephalitis but
not with other opportunistic infections of the central nervous system
(CNS) or primary brain lymphoma [20
, 45
,
46
]. In addition, increased CNS expression of MIP-1
and MIP-1ß has been reported in AIDS patients in association with
local infection of macrophages or microglia [47
]. Taken
together, these studies suggest a potential role for CC chemokines, and
MCP-1 in particular, in controlling HIV infection in the CNS, likely
acting by recruiting monocytes from the bloodstream, as observed in
animal models [48
, 49
]. In support of this
hypothesis, we have recently demonstrated that productive infection of
MDM by HIV strains with different usage of chemokine co-receptors leads
to a strong up-regulation of MCP-1 expression and secretion
[50
], whereas others have demonstrated a similar effect
in primary fetal astrocytes stimulated with HIV-1 Tat
[51
].
In conclusion, our study fully supports the importance, but also the complexity of the role played by different CC chemokines controlling HIV infection and spreading, by providing direct evidence of their role in modulating viral replication in naturally infected CD4+ cells.
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