Inhibition of HIV-1 replication by GB virus C infection through increases in RANTES, MIP-1alpha, MIP-1beta, and SDF-1

Background People coinfected with HIV and GB virus C (GBV-C) have lower mortality than HIV-positive individuals without GBV-C infection. HIV uses either of the chemokine receptors CCR5 and CXCR4 for entry into CD4-positive cells. Longer survival in HIV-positive individuals is associated with high serum concentrations of ligands for CCR5 (RANTES [regulated on activation, normal T-cell expressed and secreted] and macrophage inflammatory proteins [MIP] 1alpha and 1beta) and CXCR4 (stromal-derived factor [SDF-1]), and with decreased expression of CCR5 on lymphocytes. Methods Peripheral-blood mononuclear cells were coinfected with GBV-C and HIV, and HIV replication was monitored by measuring infectivity and HIV p24 antigen production. Chemokine secretion was measured by ELISA, chemokine-receptor expression by flow cytometry, and cellular chemokine mRNA expression by differential hybridisation. Findings GBV-C infection of peripheral-blood mononuclear cells resulted in decreased replication of both clinical and laboratory HIV strains that use either CCR5 or CXCR4 as their coreceptor. Inhibition was related to the dose and timing of the GBV-C infection. Expression of mRNA for RANTES, MIP-1alpha, MIP-1beta, and SDF-1 and secretion of the chemokines into culture supernatants were higher in GBV-C-infected cells than in mock-infected cells. The inhibitory effect of GBV-C on HIV replication was blocked by incubation with neutralising antibodies against the relevant chemokines, and surface expression of CCR5 was significantly lower in GBV-C-infected cells than in mock-infected cells. Interpretation GBV-C induces HIV-inhibitory chemokines and reduces expression of the HIV coreceptor CCR5 in vitro. This study provides insight into the epidemiological association between GBV-C infection and longer survival in HIV-infected individuals.     

Monocyte chemoattractant protein-2 (CC chemokine ligand 8) inhibits replication of human immunodeficiency virus type 1 via CC chemokine receptor 5

CC chemokine receptor 5 (CCR5) is a coreceptor for cellular entry of monocyte-tropic (R5) strains of human immunodeficiency virus (HIV) type 1, which has been implicated as the predominant phenotype of HIV in early infection. The CCR5 agonists macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation, normally T cell-expressed and -secreted) have been shown to block replication of R5 virus in vitro and have gained attention as potential antiviral factors. However, a few reports have suggested that other chemokines may also block R5 HIV-1, including monocyte chemoattractant protein (MCP)-2 (CC chemokine ligand 8). We demonstrate that MCP-2 specifically inhibits replication of R5 HIV-1 and that this activity is additive to that of RANTES. Furthermore, MCP-2 induces a robust, pertussis toxin-sensitive calcium flux in primary lymphocytes, and cross-desensitization studies indicate that MCP-2 acts via CCR5. These data confirm that MCP-2 is a ligand for CCR5 on CD4(+) lymphocytes and can specifically block R5 HIV-1.     

Cerebrospinal fluid beta chemokine concentrations in neurocognitively impaired individuals infected with human immunodeficiency virus type 1.

Macrophages express the chemokine receptor CCR-5, a coreceptor for human immunodeficiency virus (HIV) entry. This receptor is ligated by beta chemokines, which influence HIV type 1 (HIV-1) replication in CCR-5-bearing cells in vitro and could influence the course of infection in the central nervous system. Cerebrospinal fluid (CSF) samples from 73 HIV-infected men were assayed for macrophage inflammatory protein-1 alpha (MIP-1alpha), MIP-1beta, and regulated upon activation, normal T cell expressed and secreted (RANTES). Distributions of all three were positively skewed. CSF chemokine concentrations were correlated with each other and were higher in demented patients. In a multivariate analysis, demented subjects were more likely to have detectable CSF MIP-1alpha, elevated CSF HIV RNA levels, and lower CD4+ cell counts. However, among those with detectable CSF MIP-1alpha, levels were lower in demented patients. CSF beta chemokine elevation is consistent with the macrophage activation known to occur in dementia and with studies of beta chemokine mRNA expression in the brain. Low, but detectable, levels of CSF MIP-1alpha were strongly associated with dementia, suggesting that higher levels may have neuroprotective effects.     

HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling.

Human immunodeficiency virus type 1 (HIV-1) uses the chemokine receptors CCR5 and CXCR4 as coreceptors for entry. It was recently demonstrated that HIV-1 glycoprotein 120 (gp120) elevated calcium and activated several ionic signaling responses in primary human macrophages, which are important targets for HIV-1 in vivo. This study shows that chemokine receptor engagement by both CCR5-dependent (R5) and CXCR4-dependent (X4) gp120 led to rapid phosphorylation of the focal adhesion-related tyrosine kinase Pyk2 in macrophages. Pyk2 phosphorylation was also induced by macrophage inflammatory protein-1beta (MIP-1beta) and stromal cell-derived factor-1alpha, chemokine ligands for CCR5 and CXCR4. Activation was blocked by EGTA and by a potent blocker of calcium release-activated Ca++ (CRAC) channels, but was insensitive to pertussis toxin (PTX), implicating CRAC-mediated extracellular Ca++ influx but not Galpha(i) protein-dependent mechanisms. Coreceptor engagement by gp120 and chemokines also activated 2 members of the mitogen-activated protein kinase (MAPK) superfamily, c-Jun amino-terminal kinase/stress-activated protein kinase and p38 MAPK. Furthermore, gp120-stimulated macrophages secreted the chemokines monocyte chemotactic protein-1 and MIP-1beta in a manner that was dependent on MAPK activation. Thus, the gp120 signaling cascade in macrophages includes coreceptor binding, PTX-insensitive signal transduction, ionic signaling including Ca++ influx, and activation of Pyk2 and MAPK pathways, and leads to secretion of inflammatory mediators. HIV-1 Env signaling through these pathways may contribute to dysregulation of uninfected macrophage functions, new target cell recruitment, or modulation of macrophage infection.     

C-C chemokine profile of cord blood mononuclear cells: selective defect in RANTES production

Three C-C chemokines inhibit human immunodeficiency virus (HIV) entry into macrophages: macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and regulated-upon activation, normal T-cell expressed and secreted (RANTES). We studied the ability of placental cord blood mononuclear cells (CBMC) to secrete these C-C chemokines in comparison to adult blood mononuclear cells (ABMC). CBMC had diminished ability to secrete RANTES, as determined by enzyme-linked immunosorbent assay. Secretion of MIP-1alpha and MIP-1beta were similar in CBMC and ABMC. Whereas MIP-1alpha and MIP-1beta secretion were comparable in monocytes and lymphocytes, RANTES was secreted primarily by lymphocytes. Flow cytometric analysis of RANTES expression showed diminished intracellular RANTES expression in cord blood lymphocytes (CBL) compared to adult (peripheral) blood lymphocytes (ABL). A subset analysis of RANTES-producing CBL and ABL demonstrated that RANTES was produced predominantly by CD8+/CD45RO+ cells. CBL had a reduced proportion of CD8+/CD45RO+ cells compared with ABL, which may account for the diminished RANTES secretion by CBMC. These results may be relevant to the pathogenesis of perinatal HIV infection. (Blood. 2000;95:715-718)     

Activation of beta-chemokines and CCR5 in persons infected with human immunodeficiency virus type 1 and tuberculosis

Tuberculosis (TB) in human immunodeficiency virus type 1 (HIV-1)-infected persons is associated with progression of HIV-1 disease. The expression of macrophage inflammatory protein (MIP)-1alpha and CCR5 was assessed in HIV-1-infected patients with pulmonary TB (HIV-1/PTB) and without PTB (HIV-1/C), PTB patients not infected with HIV-1 (PTB), and control subjects. Mycobacterium tuberculosis (MTB)-induced MIP-1alpha production was lower in peripheral blood mononuclear cells (PBMC) of HIV-1/PTB patients than in those of PTB patients (P< .05) and was lower in PBMC of HIV-1/C patients than in those of control subjects (P< .005). However, MIP-1alpha production was higher in PBMC of HIV/PTB patients than in those of HIV-1/C patients (P< .01). The pattern of MTB-induced RANTES production was similar to that of MIP-1alpha. However, MTB induced greater expression of mRNA for CCR5 in PBMC of HIV-1/PTB patients than in those of HIV-1/C patients (P< .04). Furthermore, the MTB-induced HIV p24 antigen level in PBMC of HIV-1/PTB patients with a CD4 cell count <500 cells/microL was higher (P< .05) than that in HIV-1/C patients. Thus, perturbations in chemokine pathways in HIV-1/PTB patients may accelerate HIV-1 disease.     

Successful HAART is associated with high B-chemokine levels in chronic HIV type 1-infected patients

Chemokine receptors are used by HIV-1 for entry into CD4+ T cells. The beta-chemokines are capable of inhibiting HIV replication. This study measured beta-chemokine macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels and determined the CCR5 and CXCR4 expression on T cells in HIV-1-infected patients treated with HAART. The time of known HIV infection and time of HAART use were similar between failure and successful groups. The CD4+ T cell nadir was 163 vs. 251 cells/mm3, p = 0.07, for failure and successful groups, respectively. The successfully treated group, when compared with the failure group, had a higher median CD4+ T cells count (667 vs. 257 cells/mm3; p = 0.003) as well as higher spontaneous MIP-1alpha (median of 4390 vs. 802 pg/ml, p = 0.03) and MIP-1beta (median of 2416 vs. 1117 pg/ml, p = 0.001) levels. The untreated patients had a higher number and intensity of CCR5- and CXCR4-expressing T cells. Higher levels of chemokines were not related to nadir CD4+ T and current CD8+ T cell counts. Successfully treated patients were able to produce higher amounts of beta-chemokines and normalize the coreceptor overexpression on T cells. These findings may have clinical implications, such as a new strategy of using chemokines as adjuvants in anti-HIV therapy.     

HTLV-II down-regulates HIV-1 replication in IL-2-stimulated primary PBMC of coinfected individuals through expression of MIP-1alpha

The influence of human T-cell leukemia/lymphoma virus type II (HTLV-II) in individuals also infected with HIV-1 is poorly understood. To evaluate the reciprocal influence of HTLV-II and HIV-1 infection, primary peripheral blood mononuclear cell (PBMC) cultures from coinfected individuals were established in the presence of interleukin 2 (IL-2). In these cultures, the kinetics of HTLV-II replication always preceded those of HIV-1. Noteworthy, the kinetics of HIV-1 production were inversely correlated to the HTLV-II proviral load in vivo and its replication ex vivo. These observations suggested a potential interaction between the 2 retroviruses. In this regard, the levels of IL-2, IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured in the same coinfected PBMC cultures. Endogenous IL-2 was not produced, whereas IL-6 and TNF-alpha were secreted at levels compatible with their known ability to up-regulate HIV-1 expression. The HIV-suppressive CC-chemokines RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta were also determined in IL-2-stimulated PBMC cultures. Of interest, their kinetics and concentrations were inversely related to those of HIV-1 replication. Experiments were performed in which CD8(+) T cells or PBMCs from HTLV-II monoinfected individuals were cocultivated with CD4(+) T cells from HIV-1 monoinfected individuals separated by a semipermeable membrane in the presence or absence of antichemokine neutralizing antibodies. The results indicate that HTLV-II can interfere with the replicative potential of HIV-1 by up-regulating viral suppressive CC-chemokines and, in particular, MIP-1alpha. This study is the first report indicating that HTLV-II can influence HIV replication, at least in vitro, via up-regulation of HIV-suppressive chemokines. (Blood. 2000;95:2760-2769)     

Higher macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels from CD8+ T cells are associated with asymptomatic HIV-1 infection

To test the hypothesis that beta-chemokine levels may be relevant to the control of HIV in vivo, we compared RANTES, MIP-1alpha, and MIP-1beta production from purified CD8(+) T cells from 81 HIV-infected subjects and from 28 uninfected donors. Asymptomatic HIV(+) subjects produced significantly higher levels of MIP-1alpha and MIP-1beta, but not RANTES, than uninfected donors or patients that progressed to AIDS. In contrast, beta chemokines in plasma were either nondetectable or showed no correlation with clinical status. The high beta-chemokine-mediated anti-HIV activity was against the macrophage tropic isolate HIV-1(BAL), with no demonstrable effect on the replication of the T-cell tropic HIV-1(IIIB). These findings suggest that constitutive beta-chemokine production may play an important role in the outcome of HIV-1 infection.     

Expression and regulation of chemokine receptors in human natural killer cells

Using flow cytometric and RNase protection assays, this study examined the expression of chemokine receptors in nonactivated natural killer (NK) cells and compared this expression with NK cells activated with interleukin (IL)-2, which either adhered to plastic flasks (AD) or did not adhere (NA). None of the NK cell subsets expressed CXCR2, CXCR5, or CCR5. The major differences between these cells include increased expression of CXCR1, CCR1, CCR2, CCR4, CCR8, and CX(3)CR1 in AD when compared to NA or nonactivated NK cells. The chemotactic response to the CXC and CC chemokines correlated with the receptor expression except that all 3 populations responded to GRO-alpha, despite their lack of CXCR2 expression. Pretreatment of these cells with anti-CXCR2 did not inhibit the chemotactic response to GRO-alpha. In addition, nonactivated and NA cells responded to fractalkine, although they lack the expression of CX(3)CR1. This activity was not inhibited by anti-CX(3)CR1. Viral macrophage inflammatory protein (vMIP)-I, I-309, and TARC competed with the binding of (125)I-309 to AD cells with varying affinities. Transforming growth factor (TGF)-beta1 but not any other cytokine or chemokine examined including interferon (IFN)-gamma, MIP-3beta, macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC) or I-309, up-regulated the expression of CXCR3 and CXCR4 on NK cell surface. This is correlated with increased chemotaxis of NK cells treated with TGF-beta1 toward stromal cell-derived factor (SDF)-1alpha and interferon-inducible protein-10 (IP-10). Messenger RNA for lymphotactin, RANTES, MIP-1alpha, and MIP-1beta, but not IP-10, monocyte chemotactic protein (MCP)-1, IL-8, or I-309 was expressed in all 3 NK cell subsets. Our results may have implications for the dissemination of NK cells at the sites of tumor growth or viral replication. (Blood. 2001;97:367-375)     

Chemokine receptor 5 and its ligands in the immune response to murine tuberculosis

SETTING: The ability of chemokines such as macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and regulated-upon-activation, normal T cell expressed and secreted (RANTES), to attract and activate T cells and monocytes, the building blocks of the granuloma, suggests that these chemokines may have a role in modulating immune responses to Mycobacterium tuberculosis infection. OBJECTIVE: We hypothesized that the chemokine receptor 5 (CCR5) ligands, MIP-1alpha, MIP-1beta and RANTES, are virulence correlates in M. tuberculosis infection and are indispensable to granuloma formation. DESIGN: The ability of virulent (H37Rv) and avirulent (H37Ra) strains of M. tuberculosis to induce chemokine production in vivo and in vitro was determined at protein and mRNA levels. We also compared bacterial burden, and granuloma numbers and size in H37Rv-infected CCR5-/- or wild-type C57BL/6 mice. RESULTS: In vivo, lung mRNA and protein measurements of MIP-1alpha, MIP-1beta and RANTES indicate significantly higher (p<0.05) values (days 14-28) in the H37Rv-infected than the H37Ra-infected mice. This is consistent with a higher infection burden of the virulent strain. However, in vitro alveolar macrophage stimulation by H37Rv or H37Ra yielded no significant differences in production of the three chemokines at all time points. Histological analysis of granulomas did not show any significant differences in granuloma numbers, size and M. tuberculosis growth in CCR5-/- compared to wild-type mice. CONCLUSIONS: The production of the CCR5 ligands, MIP-1alpha, MIP-1beta, and RANTES, does not clearly correlate with virulence of M. tuberculosis. These ligands and their receptors may not be indispensable to the development of granulomas in murine tuberculosis.     

Induction of G1 cycle arrest in T lymphocytes results in increased extracellular levels of beta-chemokines: a strategy to inhibit R5 HIV-1

The beta-chemokines RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta are the natural ligands of the HIV-1 coreceptor CCR5 and compete with the virus for receptor binding. We show that secretion of the beta-chemokines by activated lymphocytes starts before cellular DNA synthesis is detected and demonstrate that transient prolongation of the G(1) phase of the cell cycle by treatment with cytostatic drugs results in increased levels of the three chemokines in culture supernatants. Supernatants collected from peripheral blood mononuclear cells exposed to hydroxyurea, which arrests the cell cycle in late G(1), contained high levels of beta-chemokines. These supernatants were able to inhibit HIV-1 replication when added to cultures of infected lymphocytes. The observed antiviral effect likely was due to the increased levels of beta-chemokines RANTES, MIP-1alpha, and MIP-1beta because (i) supernatants greatly inhibited the replication of HIV-1 BaL, whereas they affected HIV-1 IIIb replication only slightly; (ii) neutralizing antibodies against the chemokines abrogated the antiviral effect of the supernatants; and (iii) the hydroxyurea concentrations shown to up-regulate chemokine levels were not sufficient to inhibit virus replication by depletion of intracellular nucleotide pools. Although antiviral properties have been reported previously for the cytostatic agents shown here to up-regulate beta-chemokine levels, our results provide an additional mechanism by which these drugs may exert antiviral activity. In summary, increased extracellular levels of anti-HIV-1 beta-chemokines resulting from transient prolongation of the G(1) phase of the lymphocyte cell cycle by treatment with cytostatic drugs may help to control the replication of CCR5-using strains of HIV-1.     

Reduced CC chemokine receptor (CCR) 1 and CCR5 surface expression on peripheral blood T lymphocytes from patients with chronic hepatitis C infection

T cell recruitment to the infected liver is an essential step for the efficient elimination of hepatitis viruses. The surface expression of CC chemokine receptor (CCR) 1, CCR4, and CCR5 on peripheral blood T lymphocytes and their responsiveness to the chemokines macrophage inflammatory proteins (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation, normally T cell-expressed and secreted) was analyzed in patients with chronic hepatitis C and hepatitis B infection and compared with healthy subjects. Although CCR4 surface expression was not altered, hepatitis C virus (HCV)-infected patients had lower proportions of CD8 T cells with CCR1 and CCR5 surface expression (P<.05). Migration of CD8 T cells in response to MIP-1alpha, MIP-1beta, and RANTES was significantly reduced in HCV-infected patients (P<.05). Intracellular CCR1 and CCR5 protein and messenger RNA levels in peripheral blood T cells did not indicate reduced chemokine receptor biosynthesis in hepatitis C infection. Thus, chronic hepatitis C, but not hepatitis B, infection alters surface expression of distinct CCRs, resulting in lower CC chemokine responsiveness.     

CD40-activated macrophages become highly susceptible to X4 strains of human immunodeficiency virus type 1

Activating cells of the immune system may stimulate human immunodeficiency virus type 1 (HIV-1) replication and contribute to select pathogenic variants in vivo. Here, we examined the possible effect of a major pathway of immune activation, CD40 interaction with its ligand (CD40L), on the susceptibility of monocyte-derived macrophages (MDMs) to various HIV-1 strains. Stimulation of MDMs with CD40L led to reduced replication of R5 HIV-1(Ba-L), whereas this strongly enhanced the replication of X4 HIV-1(Lai) as well as of X4 primary isolates, and this was associated with strong cytopathic effects. The replication of X4 strains was inhibited by stromal cell-derived factor 1, an indication of the restricted usage of CXCR4 as virus coreceptor in this case. CD40L induced the activation of mitogen-activated protein kinases ERK1/ERK2 and stimulated MDMs to secrete RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, interleukin 6 (IL-6), IL-1beta, and tumor necrosis factor alpha. From this data, it may be hypothesized that activated macrophages represent a favorable environment for the replication of classically T lymphocyte-tropic X4 variants and, thus, may contribute significantly to the selection of such variants at late stages of clinical HIV-1 infection.     

Highly active antiretroviral therapy normalizes the potential for MIP-1alpha production in HIV infection

DESIGN: The CC chemokines RANTES, MIP-1alpha and MIP-1beta are ligands for CCR5, which has been identified as the principal co-receptor for macrophage tropic strains of HIV-1. This study investigated whether the inducible levels of RANTES, MIP-1alpha and MIP-1beta produced by cultured whole blood samples related to different rates of progression of HIV infection and to the introduction of Nelfinavir-based highly active anti-retroviral therapy (HAART). METHODS: Study subjects were HIV-positive and categorized as "slow progressors" (n= 8) or as "fast progressors" (n= 7); the latter group were treated with HAART. MIP-1alpha, MIP-1beta and RANTES production was determined using commercial ELISA kits. RESULTS: The inducible production of MIP-1alpha by whole blood cells in culture was significantly depressed in patients starting therapy compared with "slow progressors" and "normal donors". The levels of MIP-1alpha significantly increased with therapy at 12 weeks compared with pre-HAART levels (P= O.05) and became comparable to that of "normals" and "slow progressors". Differences in the inducible levels of MIP-1beta and RANTES for the separate subject groups were not significant. CONCLUSIONS: The increase in inducible MIP-1alpha production following HAART might suggest a role for the chemokines in HIV disease, either for monitoring the outcome of therapy of HIV disease, or as a direct therapeutic intervention.     

Phosphoantigen-reactive Vgamma9Vdelta2 T lymphocytes suppress in vitro human immunodeficiency virus type 1 replication by cell-released antiviral factors including CC chemokines.

Vgamma9Vdelta2 T lymphocytes are broadly reactive against various intracellular pathogens and display both lytic and proliferative responses to human immunodeficiency virus (HIV)-infected cells. HIV infection of peripheral blood mononuclear cell cultures led to absolute increases in Vgamma9Vdelta2 T cells accompanied by decreased p24 levels. Strong gammadelta T cell activation with nonpeptidic mycobacterial phosphoantigens (TUBAg1 extract or synthetic isopentenyl pyrophosphate) resulted in potent inhibition of HIV replication through soluble released factors. Subsequent analyses showed that phosphoantigen-activated gammadelta T cells produced substantial amounts of beta-chemokines (macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and regulated-on-activation, normal T-cell-expressed and -secreted beta-chemokine [RANTES]), which represent the natural ligand for the CCR5 HIV coreceptor. Accordingly, anti-beta-chemokine antibodies neutralized the inhibition of monocytotropic HIV strains by gammadelta T cell-released factors. Moreover, a T-tropic HIV strain using the CXCR4 coreceptor for virus entry was potently inhibited. Together, these data reveal that phosphoantigen-activated gammadelta T cells are an important source of CC chemokines and may suppress HIV replication through cell-released antiviral factors.     

Sustained suppression of plasma HIV RNA is associated with an increase in the production of mitogen-induced MIP-1alpha and MIP-1beta.

The chemokine receptor CCR5 has been shown to be a major coreceptor for HIV-1. The chemokines that bind to this receptor (MIP-1alpha, MIP-1beta, and RANTES) are potent inhibitors of HIV replication and may play an important role in the pathophysiology of HIV disease. We investigated the effect of potent antiretroviral therapy (ritonavir and saquinavir) on the production of MIP-1alpha, MIP-1beta, and RANTES in 19 HIV-infected patients who had sustained decreases in plasma HIV RNA levels (<200 copies/ml). Chemokine concentrations were measured in serum, plasma, and PHA-stimulated PBMCs at baseline and 24 and 48 weeks after initiating therapy. MIP-1alpha, MIP-1beta, and RANTES levels in serum and plasma did not significantly change in the 48-week period. In contrast, MIP-1alpha and MIP-1beta secreted by PHA-stimulated PBMCs increased at 24 weeks, with this increase sustained at 48 weeks, whereas no significant change was observed in PHA-induced RANTES production. A significant positive correlation was found between the changes in PHA-induced chemokine production and baseline CD4+ T cell counts. These data demonstrate that sustained suppression of viral replication by potent antiretroviral therapy has a potentially beneficial effect on chemokine production and early initiation of this therapy appears to confer a more favorable chemokine profile.