CCR5 and CCL5 in metastatic colorectal cancer.

The CCR/L5 axis is known for its role in immune regulation in a variety of settings and has been shown to have dichotomous functions in cancer, influencing both tumor progression and immune responses. Battaglin et al investigated its role using genomic and transcriptomic data from several datasets of patients with advanced colorectal cancer (CRC), including patients treated on CALGB/SWOG 80405, a trial of chemotherapy plus cetuximab versus bevacizumab, as well as a larger population of patients whose CRCs underwent commercially available Caris NGS and CODEai assays. These authors showed that CCR/L5 expression was both prognostic and predictive. They reported that low expression of the CCR/L5 axis was correlated with improved survival broadly, with particular benefit in patients treated with chemotherapy plus cetuximab. They demonstrated that high expression of CCR/L5 was associated with infiltration by negatively prognostic Tregs, M1 and M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. They also showed that increased expression was correlated a wide variety of immune suppressive proteins, including PD-1, PD-L1, PD-L2, CTLA4, CD80, CD86, TIM3, IDO1, LAG3, and IFN-γ. This suggests mechanisms by which CRC resists anti-cancer immune responses. This study enhances our understanding of the role of the CCR/L5 axis in advanced CRC.

CRISPR/Cas9 genome editing of CCR5 combined with C46 HIV-1 fusion inhibitor for cellular resistant to R5 and X4 tropic HIV-1.

Hematopoietic stem-cell (HSC) transplantation using a donor with a homozygous mutation in the HIV co-receptor CCR5 (CCR5Δ32/Δ32) holds great promise as a cure for HIV-1. Previously, there were three patients that had been reported to be completely cured from HIV infection by this approach. However, finding a naturally suitable Human Leukocyte Antigen (HLA)-matched homozygous CCR5Δ32 donor is very difficult. The prevalence of this allele is only 1% in the Caucasian population. Therefore, additional sources of CCR5Δ32/Δ32 HSCs are required. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas) system is one method to mediate CCR5 knockout in HSCs that has been successfully employed as a gene editing tool in clinical trials. Additional anti-HIV-1 strategies are still required for broad-spectrum inhibition of HIV-1 replication. Here in this study, we combined an additional anti-HIV-1 therapy, which is C46, a cell membrane-anchored HIV-1 fusion inhibitor with the CRISPR/Cas9 mediated knockout CCR5. The combined HIV-1 therapeutic genes were investigated for the potential prevention of both CCR5 (R5)- and CXCR4 (X4)-tropic HIV-1 infections in the MT4CCR5 cell line. The combinatorial CRISPR/Cas9 therapies were superior compared to single method therapy for achieving the HIV-1 cure strategy and shows potential for future applications.

The CRISPR-Cas9 induced CCR5 Δ32 mutation as a potent gene therapy methodology for resistance to HIV-1 variant: a review.

Human Immunodeficiency Virus (HIV) has continuously been the greatest epidemic for humanity over a period spanning almost five decades. With no specific cure or treatment available to date despite extensive research, the C-C Chemokine Receptor 5, Delta 32 (CCR5 Δ32) allele genetic point mutation plays an imperative role in the prevention of acquired immunodeficiency syndrome (AIDS). This comprehensive study aims to review the induction of the homozygous recessive deletion genotype using the Clustered Regularly Interspaced Short Palindromic Repeats, Cas 9 Enzyme (CRISPR-Cas9), and hematopoietic stem cell transplantation under positive selection pressure for active immunity in seropositive patients' populations as the phenotype. A methodology is proposed to trigger a significant increase in the expression of Delta 32 beneficial mutant alleles within controlled modern healthcare facilities utilizing totipotent stem cells through somatic gene therapy. It acts upon two dysfunctional CCR5 genes, translating mutant G protein-coupled co-receptors, whose primary function is similar to that of C-X-C Motif Chemokine receptor 4 (CXCR4), by blocking the entry of viral RNA into the CD4+ T helper lymphocytes, halting infection and seizing viral life cycle. This modification is endemic in Northern Europe, where it naturally pertains to the Caucasian descent population samples in the form of polymorphism, p (X=0.01), where X is the probability of frequency of complete immunity against HIV-1 in population samples. The epigenetics of the single nucleotide polymorphism (SNP) are analyzed as they play a significant role in immunity distribution. Furthermore, a comparative analysis within the ethical boundaries of CRISPR-Cas9 is conducted to discuss the practical aspects and challenges of the presented methodologies and treatment alternatives. Additionally, the study assembles all available data and summarizes preexisting research while providing a promising solution to this ethical dilemma. Finally, a methodology is devised to answer the question of whether the variant-specific epidemic of AIDS caused by HIV-1 can be cured via artificially inducing immunity by CRISPR-Cas9.

A simultaneous knockout knockin genome editing strategy in HSPCs potently inhibits CCR5- and CXCR4-tropic HIV-1 infection.

Allogeneic hematopoietic stem and progenitor cell transplant (HSCT) of CCR5 null (CCR5Δ32) cells can be curative for HIV-1-infected patients. However, because allogeneic HSCT poses significant risk, CCR5Δ32 matched bone marrow donors are rare, and CCR5Δ32 transplant does not confer resistance to the CXCR4-tropic virus, it is not a viable option for most patients. We describe a targeted Cas9/AAV6-based genome editing strategy for autologous HSCT resulting in both CCR5- and CXCR4-tropic HIV-1 resistance. Edited human hematopoietic stem and progenitor cells (HSPCs) maintain multi-lineage repopulation capacity in vivo, and edited primary human T cells potently inhibit infection by both CCR5-tropic and CXCR4-tropic HIV-1. Modification rates facilitated complete loss of CCR5-tropic replication and up to a 2,000-fold decrease in CXCR4-tropic replication without CXCR4 locus disruption. This multi-factor editing strategy in HSPCs could provide a broad approach for autologous HSCT as a functional cure for both CCR5-tropic and CXCR4-tropic HIV-1 infections.

α-Synuclein triggers cofilin pathology and dendritic spine impairment via a PrPC-CCR5 dependent pathway.

Cognitive dysfunction and dementia are critical symptoms of Lewy Body dementias (LBD). Specifically, alpha-synuclein (αSyn) accumulation in the hippocampus leading to synaptic dysfunction is linked to cognitive deficits in LBD. Here, we investigated the pathological impact of αSyn on hippocampal neurons. We report that either αSyn overexpression or αSyn pre-formed fibrils (PFFs) treatment triggers the formation of cofilin-actin rods, synapse disruptors, in cultured hippocampal neurons and in the hippocampus of synucleinopathy mouse models and of LBD patients. In vivo, cofilin pathology is present concomitantly with synaptic impairment and cognitive dysfunction. Rods generation prompted by αSyn involves the co-action of the cellular prion protein (PrPC) and the chemokine receptor 5 (CCR5). Importantly, we show that CCR5 inhibition, with a clinically relevant peptide antagonist, reverts dendritic spine impairment promoted by αSyn. Collectively, we detail the cellular and molecular mechanism through which αSyn disrupts hippocampal synaptic structure and we identify CCR5 as a novel therapeutic target to prevent synaptic impairment and cognitive dysfunction in LBD.

Development and Validation of a Genotypic Assay to Quantify CXCR4- and CCR5-Tropic Human Immunodeficiency Virus Type-1 (HIV-1) Populations and a Comparison to Trofile®.

HIV-1 typically infects cells via the CD4 receptor and CCR5 or CXCR4 co-receptors. Maraviroc is a CCR5-specific viral entry inhibitor; knowledge of viral co-receptor specificity is important prior to usage. We developed and validated an economical V3-env Illumina-based assay to detect and quantify the frequency of viruses utilizing each co-receptor. Plasma from 54 HIV+ participants (subtype B) was tested. The viral template cDNA was generated from plasma RNA with unique molecular identifiers (UMIs). The sequences were aligned and collapsed by the UMIs with a custom bioinformatics pipeline. Co-receptor usage, determined by codon analysis and online phenotype predictors PSSM and Geno2pheno, were compared to existing Trofile® data. The cost of V3-UMI was tallied. The sequences interpreted by Geno2pheno using the most conservative cut-off, a 2% false-positive-rate (FPR), predicted CXCR4 usage with the greatest sensitivity (76%) and specificity (100%); PSSM and codon analysis had similar sensitivity and lower specificity. Discordant Trofile® and genotypic results were more common when participants had specimens from different dates analyzed by either assay. V3-UMI reagents cost USD$62/specimen. A batch of ≤20 specimens required 5 h of technical time across 1.5 days. V3-UMI predicts HIV tropism at a sensitivity and specificity similar to those of Trofile®, is relatively inexpensive, and could be performed by most central laboratories. The adoption of V3-UMI could expand HIV drug therapeutic options in lower-resource settings that currently do not have access to phenotypic HIV tropism testing.

Genetic haute couture to block HIV-1 at front doors.

The chemokine receptors CCR5 and CXCR4 are "front doors" for HIV-1 infection in host cells, and their targeting represents a potential solution for a cure. Dudek et al.1 now propose a new gene editing strategy to simultaneously block CCR5- and CXCR4-mediated HIV-1 entry in autologous hematopoietic stem and progenitor cells (HSPCs).

Role of CCR1/5/7 in hepatocellular carcinoma: a study on prognostic evaluation, molecular subtyping, and association with immune infiltration.

This study aims to assess the prognostic value of the C-C motif chemokine receptor (CCR) gene family in hepatocellular carcinoma (HCC) and its relationship with immune infiltration and molecular subtypes of HCC. The evaluation of the GSE14520 dataset and TCGA database confirmed the prognostic significance of CCR. Building upon the correlation between CCR1, CCR5, and CCR7 and favorable prognosis, we further validated the prognostic importance of CCR1, CCR5, and CCR7 in ICGC database and an independent cohort from Guangxi autonomous region. Then, we constructed a risk prognosis model. Additionally, we observed significant positive correlations between CCR1, CCR5, and CCR7 and the infiltration of B cells, T cells, and macrophages in HCC. Subsequently, we conducted CCK assays, Transwell assays, and colony formation assays to evaluate the molecular biological functions of CCR1, CCR5, and CCR7. These experiments further confirmed that upregulation of CCR1, CCR5, and CCR7 can individually inhibit the proliferation, migration, and stemness of HCC cells. By analyzing the relationship between expression levels and tumor mutation frequency, we discovered that patients with high CCR1 expression were more likely to be classified as non-proliferative HCC. Similar conclusions were observed for CCR5 and CCR7. The association of CCR1, CCR5, and CCR7 with the molecular subtypes of HCC suggests that they may serve as intermediary molecules linking immune status and molecular subtypes in HCC. In summary, CCR1, CCR5, and CCR7 have the potential to serve as prognostic biomarkers for HCC and regulate HCC progression by influencing immune cell infiltration.

Expression of monocyte chemokine receptors in diabetes after non-surgical periodontal treatment: A pilot study.

The aim of this study was to evaluate the effect of non-surgical periodontal treatment in the expression of chemokine receptors, in individuals with Periodontitis, associated or not with Diabetes. Pilot study, which included patients (n = 45) with Periodontitis, associated (n = 25) or not (n = 20) with Diabetes, submitted to the non-surgical periodontal treatment for one month. The expression of chemokine receptors CCR2, CCR5, and CX3CR1 at the mRNA level was evaluated in the peripheral mononuclear cells, as well as the expression of these receptors at the protein level was verified in monocyte subtypes (classical, intermediate, and non-classical monocytes). There was higher expression of CCR2 and CCR5 receptors at the initial visit in the group with Diabetes, with no differences for CX3CR1 (p = 0.002; p = 0.018, and p = 0.896, respectively), without differences after treatment. There was higher expression of CCR2 and CCR5 proteins in the group with Diabetes at the initial visit for classical, intermediate, and nonclassical monocytes, with no differences for CX3CR1 (CCR2: p = 0.004; p = 0.026; p = 0.024; CCR5: 0.045; p = 0.045; p = 0.013; CX3CR1: p = 0.424; p = 0.944; p = 0.392, respectively), without differences after the end of treatment. Concerning each group separately, there were reductions in the expression of CCR2 as well as CCR5 in classical, intermediate, and nonclassical monocytes, and reduction of CX3CR1 in classical monocytes after treatment in the group with Diabetes (p = 0.003; p = 0.006; p = 0.039; p = 0.007; p = 0.006; p = 0.004; p = 0.019, respectively), without differences in the group without Diabetes. The expression of the chemokine receptors CCR2 and CCR5, in patients with Periodontitis associated with Diabetes, is favorably modified after the end of the non-surgical periodontal treatment.

JAK/STAT signaling pathway affects CCR5 expression in human CD4+ T cells.

CCR5 serves as R5-tropic HIV co-receptor. Knocking out CCR5 in HIV patients, which has occurred <10 times, is believed important for cure. JAK/STAT inhibitors tofacitinib and ruxolitinib inhibit CCR5 expression in HIV+ viremic patients. We investigated the association of JAK/STAT signaling pathway with CCR5/CCR2 expression in human primary CD4+ T cells and confirmed its importance. Six of nine JAK/STAT inhibitors that reduced CCR5/CCR2 expression were identified. Inhibitor-treated CD4+ T cells were relatively resistant, specifically to R5-tropic HIV infection. Furthermore, single JAK2, STAT3, STAT5A, and STAT5B knockout and different combinations of JAK/STAT knockout significantly reduced CCR2/CCR5 expression of both RNA and protein levels, indicating that CCR5/CCR2 expression was positively regulated by JAK-STAT pathway in CD4+ T cells. Serum and glucocorticoid-regulated kinase 1 (SGK1) knockout affected CCR2/CCR5 gene expression, suggesting that SGK1 is involved in CCR2/CCR5 regulation. If cell surface CCR5 levels can be specifically and markedly down-regulated without adverse effects, that may have a major impact on the HIV cure agenda.

Legacy of a magic gene-CCR5-∆32: From discovery to clinical benefit in a generation.

The discovery of the 32-bp deletion allele of the chemokine receptor gene CCR5 showed that homozygous carriers display near-complete resistance to HIV infection, irrespective of exposure. Algorithms of molecular evolutionary theory suggested that the CCR5-∆32 mutation occurred but once in the last millennium and rose by strong selective pressure relatively recently to a ~10% allele frequency in Europeans. Several lines of evidence support the hypothesis that CCR5-∆32 was selected due to its protective influence to resist Yersinia pestis, the agent of the Black Death/bubonic plague of the 14th century. Powerful anti-AIDS entry inhibitors targeting CCR5 were developed as a treatment for HIV patients, particularly those whose systems had developed resistance to powerful anti-retroviral therapies. Homozygous CCR5-∆32/∆32 stem cell transplant donors were used to produce HIV-cleared AIDS patients in at least five "cures" of HIV infection. CCR5 has also been implicated in regulating infection with Staphylococcus aureus, in recovery from stroke, and in ablation of the fatal graft versus host disease (GVHD) in cancer transplant patients. While homozygous CCR5-∆32/32 carriers block HIV infection, alternatively they display an increased risk for encephalomyelitis and death when infected with the West Nile virus.

Toxicogenomics of the C-C chemokine receptor type 5 (CCR5): Exploring the potential impacts of chemical-CCR5 interactions on inflammation and human health.

This article explores the impact of environmental chemicals on CCR5 expression and related inflammatory responses based on curated data from the Comparative Toxicogenomics Database (CTD). A total of 143 CCR5-interacting chemicals was found, with 229 chemical interactions. Of note, 67 (29.3%) out of 229 interactions resulted in "increased expression" of CCR5 mRNA or CCR5 protein, and 42 (18.3%) chemical interactions resulted in "decreased expression". The top-5 CCR5-interacting chemicals were "Tetrachlorodibenzodioxin", "Lipopolysaccharides", "Benzo(a)pyrene", "Drugs, Chinese Herbal", and "Ethinyl Estradiol". Based on the number of interactions and importance as environmental contaminant, we then focused our analysis on Tetrachlorodibenzodioxin and Benzo(a)pyrene. There is some consistency in the data supporting an increase in CCR5 expression triggered by Tetrachlorodibenzodioxin; although data concerning CCR5-Benzo(a)pyrene interactions is limited. Considering the high linkage disequilibrium between CCR5 and CCR2 genes, we also search for chemicals that interact with both genes, which resulted in 72 interacting chemicals, representing 50.3% of the 143 CCR5-interacting chemicals and 37.5% of the 192 CCR2-interacting chemicals. In conclusion, CTD data showed that environmental contaminants indeed affect CCR5 expression, with a tendency towards increased expression. The interaction of environmental contaminants with other chemokine receptor genes may potentialize their toxic effects on the chemokine system, favoring inflammation.

Role of the CCL5 and Its Receptor, CCR5, in the Genesis of Aldosterone-Induced Hypertension, Vascular Dysfunction, and End-Organ Damage.

BACKGROUND: Aldosterone has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The functions of CCL5 (C-C motif chemokine ligand 5) and its receptor CCR5 (C-C motif chemokine receptor 5) are well known in infectious diseases, their contributions to aldosterone-induced vascular injury and hypertension remain unknown. METHODS: We analyzed the vascular profile, blood pressure, and renal damage in wild-type (CCR5+/+) and CCR5 knockout (CCR5-/-) mice treated with aldosterone (600 µg/kg per day for 14 days) while receiving 1% saline to drink. Vascular function was analyzed in aorta and mesenteric arteries, blood pressure was measured by telemetry and renal injury and inflammation were analyzed via histology and flow cytometry. Endothelial cells were used to study the molecular signaling whereby CCL5 induces endothelial dysfunction. RESULTS: Aldosterone treatment resulted in exaggerated CCL5 circulating levels and vascular CCR5 expression in CCR5+/+ mice accompanied by endothelial dysfunction, hypertension, and renal inflammation and damage. CCR5-/- mice were protected from these aldosterone-induced effects. Mechanistically, we demonstrated that CCL5 increased NOX1 (NADPH oxidase 1) expression, reactive oxygen species formation, NFκB (nuclear factor kappa B) activation, and inflammation and reduced NO production in isolated endothelial cells. These effects were abolished by antagonizing CCR5 with Maraviroc. Finally, aorta incubated with CCL5 displayed severe endothelial dysfunction, which is prevented by blocking NOX1, NFκB, or CCR5. CONCLUSIONS: Our data demonstrate that CCL5/CCR5, through activation of NFκB and NOX1, is critically involved in aldosterone-induced vascular and renal damage and hypertension placing CCL5 and CCR5 as potential therapeutic targets for conditions characterized by aldosterone excess.

Suggested mechanism of CCR5Δ32, CCR2-64I and SDF 1-3'A allele frequency change in Polish and Lithuanian gene pools from the perspective of passing time.

The study aimed to determine the frequency of the alleles associated with hereditary immune response in 16 historical populations and assess which evolutionary forces may have contributed to the observed frequency fluctuation. The analysed polymorphic sites are located in three genes - CCR5, CCR2 and SDF 1 (CXCL12). Protein products are involved in the innate immune response and are also involved in various types of infections, autoimmune diseases and tumours. The frequency of the alleles found in the DNA of the studied individuals was determined by the Sanger methodology and was compared with the data obtained for modern populations. To confirm the authenticity of the obtained results, mtDNA HVRI haplotypes of all the studied samples were obtained and compared with the genetic database of the laboratory personnel who came into contact with the studied material. Based on the variability of allele frequency, advanced biostatistical analysis was used to distinguish the effect of natural selection from genetic drift, i.e. the forces operating on the polymorphic sites studied. All procedures were performed according to the guidelines for working with ancient DNA to avoid contamination with modern DNA molecules. 681 samples from 39 archaeological sites in Poland and Lithuania dated to the 40th century BC and the 19th century were studied. The biostatistical analysis showed that the fluctuations in the frequency of CCR5Δ32 in the analysed time interval could be mainly the effect of genetic drift. Nevertheless, for CCR2-64I and SDF 1-3'A, the results confirm the suggestion of negative selection as the mechanism involved. Since all the polymorphic sites encode the elements of innate immune response that are indirectly associated with the process of an HPV infection and the development of cervical cancer, the human papillomavirus may be a good candidate for a selection coefficient affecting the frequency of CCR2-64I and SDF 1-3'A. However, for CCR5Δ32, selection was not detected despite its proven role in the molecular mechanism involved in the response to an HPV infection. The presented work seems to be the first in which the problem of the pattern of CCR5Δ32, CCR2-64I and SDF 1-3'A frequency fluctuations in a temporal perspective was discussed, proposing HPV as a factor influencing the occurrence of the CCR2 and SDF1 alleles.

Polymorphisms of CCR5, IL-6, IFN-γ and IL-10 genes in Cuban HIV/AIDS patients.

INTRODUCTION: Genetic studies have shown associations of several single nucleotide polymorphisms (SNP) with different rates of progression and variation in susceptibility to HIV infection. This study aimed to estimate the frequency of ccr5Δ32, IL-6-174G/C, IFN-γ+874T/A and IL-10-1082A/G polymorphisms in Cuban HIV-infected patients and a group of sero-discordant couples to assess their influence on risk and disease progression. METHODS: A cross-sectional study was carried out on 120 subjects registered at the Institute of Tropical Medicine «Pedro Kour¼ (IPK) and the Ameijeiras Hospital from June 2018 until December 2019. The amplification of fragments of the ccr5, IL-6, IFN-γ and IL-10 genes was performed by polymerase chain reaction followed by identification of polymorphisms using the restriction fragment length polymorphism analysis for IL-6 with the restriction enzymes Nla III. Amplification Refractory Mutation System was used for IFN-γ and IL-10 genes. RESULTS: The allelic and genotypic distributions of the genes ccr5, IL-6, IFN-γ and IL-10 did not differ significantly between the two groups. Cell counts and plasma viral load values did not differ significantly between genotypes of the ccr5, IL-6, IFN-γ and IL-10 genes. Only the IL-6 GC genotype was associated with higher viral load values. The combination of alleles of the four considered SNPs showed a highly significant increase in the risk of HIV infection for one of them, but with a very low frequency (<1%). CONCLUSION: This study contributes to evaluating the frequency of these polymorphisms and their influence on biomarkers of the progression of HIV infection in the Cuban HIV-population.

CCR5 and CCL5 gene expression in colorectal cancer: comprehensive profiling and clinical value.

BACKGROUND: The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and to determine whether CCR5/CCL5 levels could impact treatment outcomes. METHODS: 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. RESULTS: CCR5/CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5/CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5/CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5/CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone. CONCLUSIONS: Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.

CCR5 deficiency: Decreased neuronal resilience to oxidative stress and increased risk of vascular dementia.

INTRODUCTION: As the chemokine receptor5 (CCR5) may play a role in ischemia, we studied the links between CCR5 deficiency, the sensitivity of neurons to oxidative stress, and the development of dementia. METHODS: Logistic regression models with CCR5/apolipoprotein E (ApoE) polymorphisms were applied on a sample of 205 cognitively normal individuals and 189 dementia patients from Geneva. The impact of oxidative stress on Ccr5 expression and cell death was assessed in mice neurons. RESULTS: CCR5-Δ32 allele synergized with ApoEε4 as risk factor for dementia and specifically for dementia with a vascular component. We confirmed these results in an independent cohort from Italy (157 cognitively normal and 620 dementia). Carriers of the ApoEε4/CCR5-Δ32 genotype aged ≥80 years have an 11-fold greater risk of vascular-and-mixed dementia. Oxidative stress-induced cell death in Ccr5-/- mice neurons. DISCUSSION: We propose the vulnerability of CCR5-deficient neurons in response to oxidative stress as possible mechanisms contributing to dementia.

The menstrual cycle regulates migratory CD4 T-cell surveillance in the female reproductive tract via CCR5 signaling.

Despite their importance for immunity against sexually transmitted infections, the composition of female reproductive tract (FRT) memory T-cell populations in response to changes within the local tissue environment under the regulation of the menstrual cycle remains poorly defined. Here, we show that in humans and pig-tailed macaques, the cycle determines distinct clusters of differentiation 4 T-cell surveillance behaviors by subsets corresponding to migratory memory (TMM) and resident memory T cells. TMM displays tissue-itinerant trafficking characteristics, restricted distribution within the FRT microenvironment, and distinct effector responses to infection. Gene pathway analysis by RNA sequencing identified TMM-specific enrichment of genes involved in hormonal regulation and inflammatory responses. FRT T-cell subset fluctuations were discovered that synchronized to cycle-driven CCR5 signaling. Notably, oral administration of a CCR5 antagonist drug blocked TMM trafficking. Taken together, this study provides novel insights into the dynamic nature of FRT memory CD4 T cells and identifies the menstrual cycle as a key regulator of immune surveillance at the site of STI pathogen exposure.

CCR5 promoter polymorphisms associated with nonsmall cell lung cancer.

C-C chemokine receptor 5 (CCR5) plays a crucial role in the regulation of immune cell activation and migration as well as the progression of many cancers. We performed an in silico analysis using public data resources and found that the lung cancer patients with higher CCR5 expression had a notably better overall survival than those with lower CCR5 expression patients and CCR5 expression level is positive correlated with the infiltration of immune cells, such as B, CD8+ T and CD4+ T cells, in both lung adenocarcinoma and lung squamous cell cancer. In the present study, we investigated the association between the promoter polymorphism of CCR5 and nonsmall cell lung cancer (NSCLC). A case-control study of 449 NSCLC patients and 516 controls of Chinese Han population was conducted, along with polymorphism detection using a sequencing method. A dual-luciferase reporter assay system was used to analyse the transcriptional activity of CCR5 promoter variations. Our results showed that the frequency of rs1799987-AA was significantly higher in the NSCLC group than in the controls in recessive model (p = .007, OR = 1.66 95% confidence interval [CI]: 1.14-2.40, adjusted by sex and age); the G allele showed a significant associated with NSCLC in dominant model (p = .003, OR = 1.64, 95%CI: 1.18-2.28, adjusted by sex and age). Compared with haplotype H1 rs2227010-rs2734648-rs1799987-rs1799988-rs1800023-rs1800024: A-T-G-T-G-C, haplotype H5: A-G-G-T-G-C increased the risk of NSCLC by over 10-fold (p < .0001, OR = 16.09, 95%CI: 5.37-48.20, adjusted by sex and age) and notably depressed the transcriptional activity of the CCR5 promoter in 293T, A549, H1299 and HeLa cells. In conclusion, CCR5 promoter polymorphisms are significantly associated with NSCLC by affecting the transcriptional activity of the CCR5 promoter.