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Background: HIV-1 seroreversion in infants with vertically transmitted HIV-1 infection who started ART in the first months of life has been reported in only a subset of patients. However, the reason why most infants remain seropositive despite similar treatment response is not understood. Here, we assessed whether HIV-1 seroreversion in maternally infected infants is associated with genetic determinants. Methods: HIV-1-infected infants with a history of documented HIV-1 seroreversion were identified throughout Germany using a standardized questionnaire. At study entry immune reconstitution and anti-HIV-1 antibody expression were monitored as clinical parameters. To search for genetic determinants high-resolution HLA genotyping was performed. In addition, the coding sequence of the chemokine receptor CCR5 was analyzed by Sanger sequencing regarding potential mutations. Results: Patients showed normal numbers and frequencies of lymphocyte subpopulations. Five out of eight patients still had seronegative HIV-1 antibody status at study entry. HLA genotyping revealed the enrichment of HLA-DQB1*03 and DQB1*06 alleles within the patient cohort. Only one patient was found to carry a 32 bp-deletion within the CCR5 gene. Conclusion: Our results indicate that the phenotype of HIV-1 seroreversion in infants might correlate with the presence of HLA class II alleles DQB1*03 and DQB1*06. This finding supports the idea of genetic predisposition determining HIV-1 seroreversion in vertically infected infants effectively treated with ART

Location matters! The trafficking and positioning of cells within the innate and adaptive immune compartments are key features of the immune system that optimize the generation of responses to pathogens and to other inflammatory stimuli. This positioning is directed through the production of

Background Dendritic cells (DC) are important in the development of acute graft-versus-host disease (GVHD) after allogeneic hemopoietic cell transplantation (alloHCT). The trafficking of immature DC from blood to GVHD target organs is likely to be regulated by chemokine receptors. Methods We performed flow cytometry to document the expression of chemokine receptors on circulating DC and correlated the findings after alloHCT with occurrence of acute GVHD. Results In normal individuals, plasmacytoid DC (pDC) expressed high levels of CCR5, whereas the major CD16 myeloid DC subpopulation lacked CCR5. However, its expression on CD16 cells was induced by culture in allogeneic mixed lymphocyte reaction supernatant, an effect largely mediated by interferon-γ. CCR5 was expressed on a significant proportion of CD16 DC in 42 alloHCT patients, whereas it was down-regulated on pDC. The maximum percentage of CCR5CD16 DC, at any time after transplantation, correlated with acute GVHD, whereas the minimum CCR5 on pDC showed a similar correlation. Before developing signs of GVHD, the maximum percentage CCR5CD16 DC was higher in patients with GVHD grades II to IV than in GVHD grades 0 and I, whereas the minimum percentage CCR5 on pDC was lower in GVHD grades II to IV than in GVHD grades 0 and I. CCR5 levels more than 20.5% on CD16 myeloid DC and less than 22.6% on CD123 pDC correlated with subsequent GVHD grades II to IV with high sensitivities and specificities. Conclusions These observations may reflect DC activation and altered homing during the alloimmune response and could allow early diagnosis and therapeutic intervention before the clinical diagnosis of GVHD.

The pathogenic role of T cells in hypertension has been documented well in recent animal studies. However, the existence of T-cell–driven inflammation in human hypertension has not been confirmed. Therefore, we undertook immunologic characterization of T cells from patients with hypertension and measured circulating levels of C-X-C chemokine receptor type 3 chemokines, which are well-known tissue-homing chemokines for T cells. We analyzed immunologic markers on T cells from patients with hypertension by multicolor flow cytometry. We then measured circulating levels of the C-X-C chemokine receptor type 3 chemokines, monokine induced by γ interferon (IFN), IFN γ–induced protein 10, and IFN-inducible T-cell α chemoattractant, in patients with hypertension and in age- and sex-matched control subjects by the cytometric bead array method. In addition, we examined histological features of IFN-inducible T-cell α chemoattractant expression from renal biopsy specimens of patients with hypertensive nephrosclerosis and control subjects. The total T-cell population from patients with hypertension showed an increased fraction of immunosenescent, proinflammatory, cytotoxic CD8 + T cells. Circulating levels of C-X-C chemokine receptor type 3 chemokines were significantly higher in patients with hypertension than in control subjects. Furthermore, immunohistochemical staining revealed increased expression of the T-cell chemokine, IFN-inducible T-cell α chemoattractant, in the proximal and distal tubules of patients with hypertensive nephrosclerosis. Immunosenescent CD8 + T cells and C-X-C chemokine receptor type 3 chemokines are increased in human hypertension, suggesting a role for T-cell–driven inflammation in hypertension. A more detailed characterization of CD8 + T cells may offer new opportunities for the prevention and treatment of human hypertension.

For adoptive T cell therapy to be effective against solid tumors, tumor-specific T cells must be able to migrate to the tumor site. One requirement for efficient migration is that the effector cells express chemokine receptors that match the chemokines produced either by tumor or tumor-associated cells. In this study, we investigated whether the tumor trafficking of activated T cells (ATCs) bearing a chimeric antigen receptor specific for the tumor antigen GD2 (GD2-CAR) could be enhanced by forced co-expression of the chemokine receptor CCR2b, since this receptor directs migration towards CCL2, a chemokine produced by many tumors, including neuroblastoma. Neuroblastoma cell lines (SK-N-SH and SK-N-AS) and primary tumor cells isolated from six patients all secreted high levels of CCL2, but GD2-CAR transduced ATCs lacked expression of CCR2 (60%) and migrated well in vitro. We expressed firefly luciferase in CCR2b-expressing ATCs and observed improved homing (>10-fold) to CCL2-secreting neuroblastoma compared to CCR2 negative ATCs. As a result, ATCs co-modified with both CCR2b and GD2-CAR had greater anti-tumor activity in vivo.

Chemokines (i.e. chemoattractant cytokines) are a family of small secreted molecules that mediate leukocyte migration. It is becoming increasingly more evident that chemokines play an integral role in the initiation of a specific immune response. With respect to cancer, chemokines are being studied for both their role in tumor biology and as promising immunotherapy candidates. We review several areas of chemokine importance in tumor immunity and discuss the experimental evidence that is leading to the clinical use of this cytokine family in new treatment approaches for patients with cancer.

PURPOSE OF REVIEW The purpose of this review is to assess the influence of T-cell receptor clonotype diversity on the recognition and control of chronic viral infections, and specifically in the case of HIV infection. RECENT FINDINGS The latest publications have examined the role of T-cell receptor repertoires specific for dominant epitopes in the ability to recognize variants and control viremia in chronic viral infections. In the hepatitis C virus and SIV models, diverse T-cell receptor repertoires appear to limit immune escape. In HIV infection, circulating clonotypes may have different functional abilities, showing another potential advantage of diverse clonotypic repertoires. A recent study suggests that at times narrow repertoires against a conserved epitope may be effective, perhaps through the ability to cross-recognize potential epitope variants. SUMMARY The studies discussed in this review have identified T-cell receptor diversity as an important factor for understanding the immune recognition of highly variable viruses. Further studies are needed to determine whether T-cell receptor repertoire analysis of HIV epitope-specific immune responses will provide a more accurate correlate for the control of viremia than conventional immune function assays.

Streptococcus pneumoniae (the pneumococcus) is estimated to cause approximately 1 million deaths per year in children in the developing world.1 The pneumococcus is the primary cause of pneumonia and meningitis in children in the developing world1 and is the leading cause of community-acquired bacteremia in children in sub-Saharan Africa.2 The burden of invasive pneumococcal disease (IPD) has increased in areas with a high prevalence of HIV infection.3 In South Africa, the disease incidence in children younger than 2 years of age has been shown to be 73 per 100,000 children per year in HIV-uninfected children compared with 3036 per 100,000 children per year in HIV-infected children.4 Chemokines (or chemoattractant cytokines) are subdivided into 4 distinct subfamilies (CC, CXC, CX3C, and C) depending on the arrangement and number of the conserved N-terminal cysteine molecules. The CC chemokines (also called β chemokines) have the first 2 cysteine molecules adjacent, include regulated on activation normal T cells expressed and secreted (RANTES or CCL5), monocyte chemotactic protein-1 (MCP-1 or CCL2), macrophage inflammatory protein-1α (MIP-1α or CCL3) and MIP-1β (CCL4), and they preferentially attract monocytes and/or macrophages and eosinophils. The CXC chemokines (also called α chemokines) have the first 2 cysteine molecules separated by an amino acid, which includes interleukin (IL)-8 (or CXCL8), growth-related oncogene (GROα or CXCL1), and epithelial cell–derived neutrophil activating peptide (ENA-78 or CXCL5), and they preferentially attract neutrophils.5,6 Interferon-γ (IFNγ) has been demonstrated to modulate the release of chemokines in pneumococcal cell wall–stimulated mouse microglia differentially, supporting the view that activated microglia are a major intrinsic source of central nervous system (CNS) chemokine production and that IFNγ potentially regulates this microglial chemokine response pattern.7 Because chemokines are specific for particular cell types, the ratio and concentration of different chemokines in different body compartments determine the composition of the different cell types within the particular compartment. To understand the host response, IPD, more fully, it is important to gain insight into the production and regulation of chemokines at local sites of inflammation. The HIV coreceptor CCR5 also acts as a receptor for CCL3, CCL4, and CCL5, and receptor binding and CCR5-dependent inhibition of HIV infection are induced by CCL8.8 CCR2b, the receptor for CCL2 (and CCL7, CCL8, and CCL13) is also a coreceptor for HIV and is expressed on peripheral blood lymphocytes and monocytes and/or macrophages.9 In HIV infection, CC chemokines induce an inflammatory response attracting noninfected target cells to the site of active viral replication and also induce intracellular signaling that enhances viral replication.10 The aims of this study were to investigate the chemokine response to IPD in children with pneumonia and meningitis and to examine the influence of HIV infection on the chemokine response, pneumococcal bacterial loads, and outcome.

In this study, we examined the gene expression of interleukin (IL)-8, CXCR3, and CXCR4 in leukemic cells from 100 children with relapsed B-cell progenitors (BCP) acute lymphoblastic leukemia (ALL), using quantitative real-time polymerase chain reaction (RT-PCR). IL-8, CXCR3, and CXCR4 were expressed in almost all bone marrow (BM) samples. The CXCR4 expression significantly correlated with known prognostic factors at relapse: time point and site of relapse. Patients who had a combined BM relapse (n=21) had lower IL-8 and CXCR4 expression than those who had an isolated BM relapse (n=79). The CXCR3 expression was higher in female patients (n=39) than in male patients (n=61). However, this did not reach prognostic relevance in relapsed ALL.

Despite multiple exposures to HIV-1, some individuals remain uninfected. This resistance to HIV infection has been associated with homozygosity for a 32-basepair deletion in the CCR5 receptor gene. This variant is frequent in caucasians but extremely rare in Asians and Africans. Identifying variations in the CCR5 gene that affect susceptibility to HIV infection in non-caucasians is therefore of great interest. In this report, we identify 5 CCR5 coding region variants in a Chinese population. The K26R mutation is an undescribed gene variant, whereas 228delK was already found in caucasians and G106R, C178R, and R223Q were previously described in Asian populations and functionally analyzed. As the function of K26R was still unknown, we focused our work on studying its chemokine receptor activity and HIV coreceptor properties compared with wild-type CCR5 and G106R, an already analyzed mutant taken as another control. We observed that K26R displayed alteration in MIP1-beta/CCL4 and RANTES/CCL5 ligand binding and exhibited a slightly decrease for HIV coreceptor properties.

HIV-1 plasma RNA is a prognostic indicator of HIV-1, and increased levels of HIV-1 plasma RNA are associated with rapid progression to AIDS. Because chemokines and chemokine receptors are involved in the binding and entry of HIV-1, possible effects of host genetics on viral RNA levels should be visible in early infection. HIV-1 plasma RNA was measured within 2 years of seroconversion in 198 seroincident injection drug users followed in the AIDS Link to Intravenous Experience cohort. Genetic variants were identified in the chemokine receptors (CCR2, CCR5, and CCR5 promoter) and the chemokine RANTES using TaqMan and restriction fragment length polymorphism assays. Linear regression of RANTES haplotypes on early HIV-1 plasma RNA identified individuals homozygous for the RANTES R1 haplotype as having a lower viral load by almost one-half log 10 unit compared with those bearing non-RANTES R1 haplotypes (-0.43, 95% confidence interval: -0.74, -0.12). Genetic variants in RANTES may downregulate RANTES gene expression and increase early HIV-I plasma RNA. Because RANTES is a critical chemokine and competitively inhibits HIV-1 by binding to its receptor CCR5, treatment to enhance RANTES expression may assist in delaying the progression of AIDS by decreasing the initial viral load.

The authors studied the possible association between the presence of a 32-base pair deletion allele in CC chemokine receptor 5 gene [3p21] (CCR5 Delta 32 allele) and the occurrence of MS. The presence of CCR5 Delta 32 homozygotes among patients with MS indicates that the absence of CCR5 did not protect against MS. Moreover, the CCR5 Delta 32 mutation was associated with MS in HLA-DR4-positive Russians (p(corr)0.001, odds ratio [OR] = 25.0). The (CCR5 Delta 32,DR4)-positive phenotype was negatively associated with early MS onset (at agesor = 18 years) (p = 0.0115, OR = 0.1).

Objective To investigate the infectivity of T-helper (Th)1 and Th2 cells (derived from ccr5 wild-type and homozygous ccr5 Delta 32) to R5 and X4 HIV-1. Design It remains unclear whether infection of Th1 and Th2 CD4 cells by R5 and X4 viruses mirrors their co-receptor expression profile as no direct quantitation of coreceptor levels and infection has been performed. In addition, it is unknown whether the lack of CCR5 expression affects the degree of Th1/Th2 polarization. Methods Surface expression of CCR5 and CXCR4 was determined by quantitative fluorescence activated cell sorter analysis on in vitro differentiated Th1 and Th2 cells. R5 (Ba-L) and X4 (IIIB) HIV-1 isolates were used for infection studies and the efficiency of viral entry was determined by quantitative real time polymerase chain reaction detection of reverse transcribed proviral DNA. Results Cell surface density of CCR5 molecules was eight-fold higher in Th1 versus Th2 subsets (P = 0.005) whereas CXCR4 surface density was four-fold higher in Th2 versus Th1 subsets (P = 0.006). Preferential infection and entry of Th1 cells by R5 HIV-1 was not associated with preferential replication, as eventually the R5-virus replicated to a higher level in Th2 cells in spite of lower initial viral infection/entry. By contrast, Th2 cells preferentially supported X4-virus infection and replication. High beta chemokine secretion by Th1 cells was associated with a lower R5 replication rate. Conclusions Th1 and Th2 cells differ in their infection efficiency for R5 and X4 HIV-1. ccr5 Delta 32-homozygous individuals maintain the ability for Th1/Th2 polarization, i.e., the expression of CCR5 is not required for Th1/Th2 polarization.

BACKGROUND The chemokine receptor, CCR5, and its three high-affinity ligands, macrophage inflammatory protein- (MIP) 1alpha, MIP-1beta, and regulated on activation normal T cell expressed and secreted (RANTES), are expressed by infiltrating mononuclear cells during the rejection of clinical and experimental organ allografts, although the significance of these molecules in the pathogenesis of rejection has not been established. METHODS We studied intragraft events in four allograft models. First, we studied cardiac transplants in fully MHC-mismatched mice that were deficient in CCR5 or two of its ligands, MIP-1alpha or RANTES. Second we tested the effects of a neutralizing rat anti-mCCR5 monoclonal antibody on allograft survival. Third we assessed whether a subtherapeutic course of cyclosporine would potentiate enhance survival in CCR5-deficient recipients. Finally, we tested the effect of targeting CCR5 in a class II-mismatched model. RESULTS Whereas mice deficient in expression of MIP-1alpha or RANTES reject fully MHC-mismatched cardiac allografts normally, CCR5-/- mice, or CCR5+/+ mice treated with a neutralizing mAb to mCCR5, show enhanced allograft survival. MHC class II-disparate mismatched are permanently accepted in CCR5-/- but not CCR5+/+ recipients. Finally, the beneficial effects of targeting of CCR5 are markedly synergistic with the effects of cyclosporine, resulting in permanent engraftment without development of chronic rejection. CONCLUSIONS We conclude that CCR5 plays a key role in the mechanisms of host T cell and macrophage recruitment and allograft rejection, such that targeting of CCR5 clinically may be of therapeutic significance.

Chemokines may regulate the process of immune cell infiltration that is often found in pancreatic cancer. In this study, we investigated the secretion of the chemokines [interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, and RANTES (regulated on activation, normal T cell expressed and secreted)] in human pancreatic cancer cell lines. The chemokine secretion in three pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and BxPC-3) was evaluated by enzyme-linked immunosorbent assay (ELISA) and Northern blot, and the activation of nuclear factor-kappaB (NF-kappaB) and NF-IL6 was assessed by an electrophoretic gel mobility shift assay (EMSA). Without any stimulation, IL-8 secretion was detected in all cell lines, and MCP-1 secretion was detected in PANC-1 and MIA PaCa-2 cells. However, RANTES secretion was not detected in all cells. The addition of IL-1beta and tumor necrosis factor (TNF)-alpha strongly enhanced IL-8, MCP-1, and RANTES secretion; these responses were observed at the mRNA level as well as at the protein level. IL-1beta and TNF-alpha induced a rapid activation of nuclear factor (NF)-kappaB in PANC-1 cells, and the increase in chemokine mRNA expression correlated with NF-kappaB activation. The activation of NF-IL6 was modest. A blockade of NF-kappaB activation by TPCK markedly reduced the IL-1beta- and TNF-alpha-induced chemokine gene expression. Our findings indicate that chemokines are produced by pancreatic cancer cells, and suggest that these factors may contribute to the accumulation of tumor-associated immune cells. In addition, the transcriptional activation of chemokine genes in pancreatic cancer cells may be closely associated with NF-kappaB activation.

Viral entry through the blood-brain barrier (BBB) has not been fully defined and identification of coreceptors that can facilitate this phenomenon is crucial in understanding disease progression. Using a RNAse protection assay to examine chemokine receptor families simultaneously, we analyzed the total RNA of in vitro BBB cultures treated with purified preparations of HIV gp120, gp41, TAT proteins and TNF-alpha. HIV tat protein affected CCRI and CCR3 mRNA expression whereas the other viral by-products had no effect. Interestingly, TNF-alpha was able to induce CCR1, CCR3 as well as CXCR1, CXCR2, CXCR4 receptors and Burkitt's lymphoma receptor BLR2. These results suggest that HIV-induced molecules can manipulate the surface receptor expression of the BBB to allow for their preferential entry into brain.

The efficiency of CCR5 as an HIV coreceptor is strongly dependent on its level of cell surface expression. Therefore, it is of major importance to identify the factors that regulate cell surface density of CCR5. Among the chemokines that bind to CCR5, and induce its internalization, CCL5 is the most abundant in vivo. We show that the level of CCL5 production is a main factor determining CD4+ T cell surface CCR5 density.

The chemokine receptor CCR5 constitutes the major coreceptor for the macrophage-tropic strains of HIV-1. A mutant allele of the CCR5 gene called delta32 was shown to provide strong resistance to homozygotes against infection by HIV. The frequency of the delta32 allele was investigated in 2522 noninfected unrelated individuals from 16 different European populations. The delta32 allele was found in all populations studied, with a mean frequency of about 9.1%. A north-to-south gradient correlating latitude with delta32 allelic frequencies was found (r = 0.726), with highest allele frequencies in Denmark and Northern France, and the lowest allele frequencies in Corsica.

Fulminant liver failure (FLF) consists of a cascade of events beginning with a presumed uncontrolled systemic activation of the immune system. The etiology of FLF remains undefined. In this study, we demonstrate that CCR5 deficiency promotes the development of acute FLF in mice following Con A administration by preventing activated hepatic CD1d-restricted NKT cells (but not conventional T cells) from dying from activation-induced apoptosis. The resistance of CCR5-deficient NKT cells from activation-induced apoptosis following Con A administration is not due to a defective Fas-driven death pathway. Moreover, FLF in CCR5-deficient mice also correlated with hepatic CCR5-deficient NKT cells, producing more IL-4, but not IFN-γ, relative to wild-type NKT cells. Furthermore, FLF in these mice was abolished by IL-4 mAb or NK1.1 mAb treatment. We propose that CCR5 deficiency may predispose individuals to the development of FLF by preventing hepatic NKT cell apoptosis and by regulating NKT cell function, establishing a novel role for CCR5 in the development of this catastrophic liver disease that is independent of leukocyte recruitment.

The recruitment of mononuclear cells into the arterial wall is a hallmark of atherosclerotic lesion formation. It has been widely acknowledged that the infiltration with monocytes is instrumental in the initiation and progression of atherosclerosis and that this inflammatory process is also driven or sustained by a T helper type 1 (Th1) lymphocyte-mediated immune response.1 Among other proinflammatory cytokines, an abundance of chemokines has been detected in atherosclerotic lesions and has been crucially implicated in directing the recruitment of monocytes and T cells into the lesions.2,3 Notably, genetic deletion or transfer of constructs encoding antagonistic mutants has revealed the essential contribution of certain chemokines and their receptors to lesion formation and macrophage infiltration in atherosclerosis-prone mice, eg, for the prototypic MCP-1 and its receptors CCR2 and for the fractalkine receptor CX3CR.2,3 Moreover, the CCR1 and CCR5 ligand RANTES and the CXCR3 ligands Mig and IP-10 have been found in atherosclerotic lesions. CCR5 and CXCR3 are index chemokine receptors primarily expressed on Th1 T cells guiding their migration to sites of inflammation.4 Although it has become apparent that the involvement of multiple chemokines is more reflective of the robustness and complexity of the recruitment signal required rather than the redundancy of the system, the precise role of these chemokines and their receptors in atherosclerosis has remained elusive until very recently. In addition, it has been questioned whether the involvement of these chemokines corresponds to a specific recruitment of different mononuclear cell types.2,3 See page 2642 The global blockade of the RANTES receptors CCR1, CCR3, and CCR5 using the peptide antagonist Met-RANTES has been shown to reduce atherosclerotic lesion formation and macrophage infiltration.5 A 32-bp deletion in the CCR5 gene (CCR5Δ32) results in a nonfunctional receptor, and individuals that are homozygous for this deletion …

The authors investigated the association between Delta32CCR5, a mutated allele of the chemokine receptor CCR5, and disease progression in 256 patients with multiple sclerosis (MS). The mutated allele frequency in the study cohort was 7.4%, similar to that reported in the general Israeli population. Progression to disability was prolonged in Delta32CCR5 homozygotes and heterozygotes compared with MS patients with the CCR5 wild-type genotype (p0.005). Mutated CCR5 allele may be considered a favorable prognostic factor in MS.

The possible involvement of α-defensins in CD8 T-cell-mediated anti-HIV activities has been the subject of recent investigations [1–3]. HIV host defence mechanisms are partly mediated by CD8 T-cell non-cytotoxic antiviral responses [4]. Walker et al. [5] first demonstrated that this anti-HIV activity involves a soluble factor(s) designated as CD8 cell antiviral factor (CAF) whose identity remains unknown [4]. Zhang et al. [1] proposed that α-defensins are produced by CD8 T cells and contribute to CAF-mediated anti-HIV activities. In contrast, the recent studies by Mackewicz et al. [2] and Chang et al. [3] demonstrated that the α-defensins are not produced by CD8 T cells but unexpectedly were found to be expressed by monocytes [2]. As CAF-mediated anti-HIV activity is also observed for macrophages [6,7] and monocytes express α-defensins [2], we investigated the capacity of α-defensins to suppress HIV infection of macrophages. The addition of α-defensins to peripheral blood monocyte-derived macrophage cultures markedly suppressed HIV Bal replication (Fig. 1a) [8,9]. In order to determine the mechanism(s) responsible for α-defensin-mediated HIV inhibition in macrophages, we investigated whether α-defensins regulate the expression of CC-chemokines. CC-chemokines [macrophage inflammatory protein (MIP)-1α, MIP-1β and Rantes] inhibit infection by competing with HIV M-tropic strains for the CCR5 receptor on macrophages [10,11]. Our experiments demonstrated that α-defensins dramatically enhance expression (as much as a 25-fold increase) of MIP-1α and MIP-1β messenger RNA in macrophages (Fig. 1b) [12]. This increased CC-chemokine gene expression by α-defensins was further confirmed by the demonstration of increased production (as much as a 57-fold increase) of MIP-1α and MIP-1β proteins in α-defensin-treated macrophage cultures (Fig. 1c). In addition, the antibodies to CC-chemokines completely abrogated α-defensin-mediated HIV inhibition in macrophages (Fig. 1d). Our data, therefore, indicate that the α-defensin-mediated inhibition of HIV infection of macrophages is mediated through the upregulation of CC-chemokines. This pathway is distinct from the anti-HIV activity of CAF in macrophages, because CC-chemokines are not responsible for the ability of CAF to suppress HIV infection of these cells [6,7]. Fig. 1 Effect of α-defensins on HIV infection and β-chemokine expression in macrophages The biological interaction of defensins with chemokines and chemokine receptors has been documented. Defensins functionally overlap with chemokines in microbicidal activity [13]. The treatment of dendritic cells with β-defensin-2 upregulated the expression of CC-chemokines (MIP-1α and MIP-1β) and down-regulated CCR5 expression [14]. By utilizing chemokine receptors on immune cells, defensins may contribute to the regulation of host adaptive immunity against microbial invasion [15]. Taken together, our data provide evidence that α-defensins could play a role in host defence against HIV infection of macrophages. The biological interaction of α-defensins with CC-chemokines may constitute a unique mechanism of innate immunity against HIV disease.

The beneficial role of a variant of the chemokine receptor CCR2B (CCR2B-641) in the evolution of HIV-1 infection in adults is still controversial. Furthermore, no studies have been performed in HIV-1-infected children. A multicenter and prospective study of 745 infants born to HIV-1-seropositive mothers was performed. The CCR2B-641 allele was studied in 525 non-African children among whom 523 had been previously genotyped for the CCR5delta32 allele and 220 African children. Of the 745 total, 376 children were infected and 369 were uninfected. In the complete population studied, the children homozygous for the CCR2B-64I allele and the heterozygous children were found distributed equally in the infected (respectively, 1.6% and 21%) and uninfected (respectively, 1.9% and 26.3%) groups (p < .22). Among 376 infected children, the incidence of stage C symptoms (U.S. Centers for Disease Control and Prevention [CDC] classification) or the progression of severe immune deficiency (CD4

We have investigated the effects of plasma HIV RNA, CD4+ T lymphocytes and chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs. We prospectively observed during follow-up 207 HIV-infected hemophiliacs in the Hemophilia Growth and Development Study. Plasma HIV RNA was measured on cryopreserved plasma from enrollment using the Chiron Corporation bDNA (version 2.0) assay. Genoytpe variants CCR2b-641 and CCR5-delta32 were detected using standard molecular techniques. Those with the mutant allele for CCR2b, and to a lesser extent CCR5, had lower plasma HIV RNA, and higher CD4+ T lymphocytes than did those without these genetic variants. After controlling for the effects of plasma HIV RNA and CD4+ T lymphocytes, those with the CCR2b mutant allele compared with those wild-type, had a trend toward a lower risk of progression to AIDS, adjusted relative hazard of 1.94 (95% confidence interval [CI], 0.9-4.18; p = .092), and AIDS-related death, relative hazard 1.97 (95% CI, 0.98-4.00; p = .059). We conclude that plasma HIV RNA, CD4+ T lymphocytes, and CCR genotypes are correlated, and the protective affect of CCR2b against HIV disease progression is not completely explained by plasma HIV RNA or CD4+ T-lymphocyte number.