A potential antiviral role for CCR5+CD8+ T cells in children with hepatitis B.

While dysfunctional exhausted CD8+ T cells hamper viral control when children acquire hepatitis B virus (HBV) infection, it's crucial to recognize that CD8+ T cells have diverse phenotypes and functions. This study explored a subset of CD8+ T cells expressing C-C chemokine receptor type 5 (CCR5) in children with HBV infection. Thirty-six patients in the immune tolerant group, 33 patients in the immune active group, 55 patients in the combined response group, and 22 healthy control children were enrolled. The frequency, functional molecules, and effector functions of the CCR5+CD8+ T cell population in different groups were evaluated. The frequency of CCR5+CD8+ T cells correlated positively with the frequency of CCR5+CD4+ T cells and patient age, and it correlated negatively with alanine aminotransferase, aspartate transaminase, HBV DNA, hepatitis B surface antigen, and lactic dehydrogenase levels. CCR5+CD8+ T cells had higher levels of inhibitory and activated receptors and produced higher levels of IFN-γ, IL-2, and TNF-α than CCR5-CD8+ T cells. CCR5+CD8+ T cells were partially exhausted but possessed a stronger antiviral activity than CCR5-CD8+ T cells. The identification of this subset increases our understanding of CD8+ T cell functions and serves as a potential immunotherapeutic target for children with HBV infection.

CCR5 promotes the migration of pathological CD8+ T cells to the leishmanial lesions.

Cytolytic CD8+ T cells mediate immunopathology in cutaneous leishmaniasis without controlling parasites. Here, we identify factors involved in CD8+ T cell migration to the lesion that could be targeted to ameliorate disease severity. CCR5 was the most highly expressed chemokine receptor in patient lesions, and the high expression of CCL3 and CCL4, CCR5 ligands, was associated with delayed healing of lesions. To test the requirement for CCR5, Leishmania-infected Rag1-/- mice were reconstituted with CCR5-/- CD8+ T cells. We found that these mice developed smaller lesions accompanied by a reduction in CD8+ T cell numbers compared to controls. We confirmed these findings by showing that the inhibition of CCR5 with maraviroc, a selective inhibitor of CCR5, reduced lesion development without affecting the parasite burden. Together, these results reveal that CD8+ T cells migrate to leishmanial lesions in a CCR5-dependent manner and that blocking CCR5 prevents CD8+ T cell-mediated pathology.

People with HIV have higher percentages of circulating CCR5+ CD8+ T cells and lower percentages of CCR5+ regulatory T cells.

CCR5 is the main HIV co-receptor. We aimed to (1) compare CCR5 expression on immune cells between people living with HIV (PLHIV) using combination antiretroviral therapy (cART) and HIV-uninfected controls, (2) relate CCR5 expression to viral reservoir size and (3) assess determinants of CCR5 expression. This cross-sectional study included 209 PLHIV and 323 controls. Percentages of CCR5+ cells (%) and CCR5 mean fluorescence intensity assessed by flow cytometry in monocytes and lymphocyte subsets were correlated to host factors, HIV-1 cell-associated (CA)-RNA and CA-DNA, plasma inflammation markers and metabolites. Metabolic pathways were identified. PLHIV displayed higher percentages of CCR5+ monocytes and several CD8+ T cell subsets, but lower percentages of CCR5+ naive CD4+ T cells and regulatory T cells (Tregs). HIV-1 CA-DNA and CA-RNA correlated positively with percentages of CCR5+ lymphocytes. Metabolome analysis revealed three pathways involved in energy metabolism associated with percentage of CCR5+ CD8+ T cells in PLHIV. Our results indicate that CCR5 is differently expressed on various circulating immune cells in PLHIV. Hence, cell-trafficking of CD8+ T cells and Tregs may be altered in PLHIV. Associations between energy pathways and percentage of CCR5+ CD8+ T cells in PLHIV suggest higher energy demand of these cells in PLHIV.

CCR5 as a Coreceptor for Human Immunodeficiency Virus and Simian Immunodeficiency Viruses: A Prototypic Love-Hate Affair.

CCR5, a chemokine receptor central for orchestrating lymphocyte/cell migration to the sites of inflammation and to the immunosurveillance, is involved in the pathogenesis of a wide spectrum of health conditions, including inflammatory diseases, viral infections, cancers and autoimmune diseases. CCR5 is also the primary coreceptor for the human immunodeficiency viruses (HIVs), supporting its entry into CD4+ T lymphocytes upon transmission and in the early stages of infection in humans. A natural loss-of-function mutation CCR5-Δ32, preventing the mutated protein expression on the cell surface, renders homozygous carriers of the null allele resistant to HIV-1 infection. This phenomenon was leveraged in the development of therapies and cure strategies for AIDS. Meanwhile, over 40 African nonhuman primate species are long-term hosts of simian immunodeficiency virus (SIV), an ancestral family of viruses that give rise to the pandemic CCR5 (R5)-tropic HIV-1. Many natural hosts typically do not progress to immunodeficiency upon the SIV infection. They have developed various strategies to minimize the SIV-related pathogenesis and disease progression, including an array of mechanisms employing modulation of the CCR5 receptor activity: (i) deletion mutations abrogating the CCR5 surface expression and conferring resistance to infection in null homozygotes; (ii) downregulation of CCR5 expression on CD4+ T cells, particularly memory cells and cells at the mucosal sites, preventing SIV from infecting and killing cells important for the maintenance of immune homeostasis, (iii) delayed onset of CCR5 expression on the CD4+ T cells during ontogenetic development that protects the offspring from vertical transmission of the virus. These host adaptations, aimed at lowering the availability of target CCR5+ CD4+ T cells through CCR5 downregulation, were countered by SIV, which evolved to alter the entry coreceptor usage toward infecting different CD4+ T-cell subpopulations that support viral replication yet without disruption of host immune homeostasis. These natural strategies against SIV/HIV-1 infection, involving control of CCR5 function, inspired therapeutic approaches against HIV-1 disease, employing CCR5 coreceptor blocking as well as gene editing and silencing of CCR5. Given the pleiotropic role of CCR5 in health beyond immune disease, the precision as well as costs and benefits of such interventions needs to be carefully considered.

Dual role for CXCR3 and CCR5 in asthmatic type 1 inflammation.

BACKGROUND: Many patients with severe asthma (SA) fail to respond to type 2 inflammation-targeted therapies. We previously identified a cohort of subjects with SA expressing type 1 inflammation manifesting with IFN-γ expression and variable type 2 responses. OBJECTIVE: We investigated the role of the chemotactic receptors C-X-C chemokine receptor 3 (CXCR3) and C-C chemokine receptor 5 (CCR5) in establishing type 1 inflammation in SA. METHODS: Bronchoalveolar lavage microarray data from the Severe Asthma Research Program I/II were analyzed for pathway expression and paired with clinical parameters. Wild-type, Cxcr3-/-, and Ccr5-/- mice were exposed to a type 1-high SA model with analysis of whole lung gene expression and histology. Wild-type and Cxcr3-/- mice were treated with a US Food and Drug Administration-approved CCR5 inhibitor (maraviroc) with assessment of airway resistance, inflammatory cell recruitment by flow cytometry, whole lung gene expression, and histology. RESULTS: A cohort of subjects with increased IFN-γ expression showed higher asthma severity. IFN-γ expression was correlated with CXCR3 and CCR5 expression, but in Cxcr3-/- and Ccr5-/- mice type 1 inflammation was preserved in a murine SA model, most likely owing to compensation by the other pathway. Incorporation of maraviroc into the experimental model blunted airway hyperreactivity despite only mild effects on lung inflammation. CONCLUSIONS: IFNG expression in asthmatic airways was strongly correlated with expression of both the chemokine receptors CXCR3 and CCR5. Although these pathways provide redundancy for establishing type 1 lung inflammation, inhibition of the CCL5/CCR5 pathway with maraviroc provided unique benefits in reducing airway hyperreactivity. Targeting this pathway may be a novel approach for improving lung function in individuals with type 1-high asthma.

CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab.

CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes.

Complement Potentiates Immune Sensing of HIV-1 and Early Type I Interferon Responses.

Complement-opsonized HIV-1 triggers efficient antiviral type I interferon (IFN) responses in dendritic cells (DCs), which play an important role in protective responses at the earliest stages in retroviral infection. In contrast, HIV-1 suppresses or escapes sensing by STING- and MAVS-associated sensors. Here, we identified a complement receptor-mediated sensing pathway, where DCs are activated in CCR5/RLR (RIG-I/MDA5)/MAVS/TBK1-dependent fashion. Increased fusion of complement-opsonized HIV-1 via complement receptor 4 and CCR5 leads to increased incoming HIV-1 RNA in the cytoplasm, sensed by a nonredundant cooperative effect of RIG-I and MDA5. Moreover, complement-opsonized HIV-1 down-modulated the MAVS-suppressive Raf-1/PLK1 pathway, thereby opening the antiviral recognition pathway via MAVS. This in turn was followed by MAVS aggregation and subsequent TBK1/IRF3/NF-κB activation in DCs exposed to complement- but not non-opsonized HIV-1. Our data strongly suggest that complement is important in the induction of efficient antiviral immune responses by preventing HIV-1 suppressive mechanisms as well as inducing specific cytosolic sensors. IMPORTANCE Importantly, our study highlights an unusual target on DCs-the α chain of complement receptor 4 (CR4) (CD11c)-for therapeutic interventions in HIV-1 treatment. Targeting CD11c on DCs mediated a potent antiviral immune response via clustering of CR4 and CCR5 and subsequent opening of an antiviral recognition pathway in DCs via MAVS. This novel finding might provide novel tools for specifically boosting endogenous antiviral immunity via CR4, abundantly expressed on multiple DC subsets.

CCR5 is a prognostic biomarker and an immune regulator for triple negative breast cancer.

This study aims to explore the clinical implications and potential mechanistic functions of CCR5 in triple negative breast cancer. Briefly, we demonstrated that CCR5 is overexpressed in TNBC and is associated with better prognosis of TNBC. CCR5 expression is positively correlated with tumor immune cell infiltration and tumor immune response related pathways. Multi-omics data analyses identified CCR5 associated genomic and proteomic changes. CCR5 overexpression was associated with better overall survival in TNBC patients with TP53 mutation. We also summarized the latest findings on ICB efficacy related genes and explored the association between CCR5 and those genes. These results indicated that CCR5 is a potential tumor suppressor gene and individualized therapeutic strategy could be established based on multi-omics background and expression pattern of ICB related genes. In conclusion, CCR5 is associated with better survival of TNBC patients with TP53 mutation, which may exert its roles through tumor immune environment.

Bioinformatics-based study to identify immune infiltration and inflammatory-related hub genes as biomarkers for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose principal pathological change is aggressive chronic synovial inflammation; however, the specific etiology and pathogenesis have not been fully elucidated. We downloaded the synovial tissue gene expression profiles of four human knees from the Gene Expression Omnibus database, analyzed the differentially expressed genes in the normal and RA groups, and assessed their enrichment in functions and pathways using bioinformatics methods and the STRING online database to establish protein-protein interaction networks. Cytoscape software was used to obtain 10 hub genes; receiver operating characteristic (ROC) curves were calculated for each hub gene and differential expression analysis of the two groups of hub genes. The CIBERSORT algorithm was used to impute immune infiltration. We identified the signaling pathways that play important roles in RA and 10 hub genes: Ccr1, Ccr2, Ccr5, Ccr7, Cxcl5, Cxcl6, Cxcl13, Ccl13, Adcy2, and Pnoc. The diagnostic value of these 10 hub genes for RA was confirmed using ROC curves and expression analysis. Adcy2, Cxcl13, and Ccr5 are strongly associated with RA development. The study also revealed that the differential infiltration profile of different inflammatory immune cells in the synovial tissue of RA is an extremely critical factor in RA progression. This study may contribute to the understanding of signaling pathways and biological processes associated with RA and the role of inflammatory immune infiltration in the pathogenesis of RA. In addition, this study shows that Adcy2, Cxcl13, and Ccr5 have the potential to be biomarkers for RA treatment.

Co-receptor signaling in the pathogenesis of neuroHIV.

The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.

CD101 genetic variants modify regulatory and conventional T cell phenotypes and functions.

We recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets.

Antibody Conjugates for Targeted Therapy Against HIV-1 as an Emerging Tool for HIV-1 Cure.

Although advances in antiretroviral therapy (ART) have significantly improved the life expectancy of people living with HIV-1 (PLWH) by suppressing HIV-1 replication, a cure for HIV/AIDS remains elusive. Recent findings of the emergence of drug resistance against various ART have resulted in an increased number of treatment failures, thus the development of novel strategies for HIV-1 cure is of immediate need. Antibody-based therapy is a well-established tool in the treatment of various diseases and the engineering of new antibody derivatives is expanding the realms of its application. An antibody-based carrier of anti-HIV-1 molecules, or antibody conjugates (ACs), could address the limitations of current HIV-1 ART by decreasing possible off-target effects, reduce toxicity, increasing the therapeutic index, and lowering production costs. Broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency against HIV-1 are currently being explored to prevent or treat HIV-1 infection in the clinic. Moreover, bNAbs can be engineered to deliver cytotoxic or immune regulating molecules as ACs, further increasing its therapeutic potential for HIV-1 cure. ACs are currently an important component of anticancer treatment with several FDA-approved constructs, however, to date, no ACs are approved to treat viral infections. This review aims to outline the development of AC for HIV-1 cure, examine the variety of carriers and payloads used, and discuss the potential of ACs in the current HIV-1 cure landscape.

CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells.

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8+ tissue-resident memory CD8+ T (CD8+ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69+CD103-CD8+ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8+ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8+ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69+CD8+ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8+ Trm in fibrosis resolution.

Recent developments in CCR5 regulation for HIV cure.

Acquired immunodeficiency syndrome (AIDS) has affected millions of people worldwide. The human immunodeficiency virus (HIV) which infects T cells by using CD4 as its main receptor. Currently different treatments are available against HIV infection which can improve life expectancy of the patient but still it remains incurable. CCR5, which is also required as a co-receptor by majority of HIV strains for entry into the target cells, is now being targeted for gene therapy to develop HIV resistance in patients. In this review, we discuss different strategies that are being adapted for CCR5-gene disruption in CD4+ T cells and in hematopoietic stem cells (HSCs) to generate a HIV-resistant immune system in infected individuals. If CCR5 gene that can shape HIV-resistant T cells, it will aim in new approaches in clinical trials. But these techniques have certain weaknesses and disadvantages, and will need to be paired with other strategies to form a full HIV remedy. There is also a need to establish methods to help deter HIV re-emergence following targeted CCR5 therapy. But ultimately, this brought us a better knowledge of the road to HIV treatment.

Chemokine Receptor 5 Antagonism Causes Reduction in Joint Inflammation in a Collagen-Induced Arthritis Mouse Model.

Rheumatoid arthritis (RA) is a chronic inflammatory disease mainly affecting the synovial joints. A highly potent antagonist of C-C chemokine receptor 5 (CCR5), maraviroc (MVC), plays an essential role in treating several infectious diseases but has not yet been evaluated for its potential effects on RA development. This study focused on evaluating the therapeutic potential of MVC on collagen-induced arthritis (CIA) in DBA/1J mice. Following CIA induction, animals were treated intraperitoneally with MVC (50 mg/kg) daily from day 21 until day 35 and evaluated for clinical score and histopathological changes in arthritic inflammation. We further investigated the effect of MVC on Th9 (IL-9, IRF-4, and GATA3) and Th17 (IL-21R, IL-17A, and RORγT) cells, TNF-α, and RANTES in CD8+ T cells in the spleen using flow cytometry. We also assessed the effect of MVC on mRNA and protein levels of IL-9, IL-17A, RORγT, and GATA3 in knee tissues using RT-PCR and western blot analysis. MVC treatment in CIA mice attenuated the clinical and histological severity of inflammatory arthritis, and it substantially decreased IL-9, IRF4, IL-21R, IL-17A, RORγT, TNF-α, and RANTES production but increased GATA3 production in CD8+ T cells. We further observed that MVC treatment decreased IL-9, IL-17A, and RORγt mRNA and protein levels and increased those of GATA3. This study elucidates the capacity of MVC to ameliorate the clinical and histological signs of CIA by reducing pro-inflammatory responses, suggesting that MVC may have novel therapeutic uses in the treatment of RA.

B Lymphocytes, but Not Dendritic Cells, Efficiently HIV-1 Trans Infect Naive CD4+ T Cells: Implications for the Viral Reservoir.

Insight into the establishment and maintenance of HIV-1 infection in resting CD4+ T cell subsets is critical for the development of therapeutics targeting the HIV-1 reservoir. Although the frequency of HIV-1 infection, as quantified by the frequency of HIV-1 DNA, is lower in CD4+ naive T cells (TN) than in the memory T cell subsets, recent studies have shown that TN harbor a large pool of replication-competent virus. Interestingly, however, TN are highly resistant to direct (cis) HIV-1 infection in vitro, in particular to R5-tropic HIV-1, as TN do not express CCR5. In this study, we investigated whether TN could be efficiently HIV-1 trans infected by professional antigen-presenting B lymphocytes and myeloid dendritic cells (DC) in the absence of global T cell activation. We found that B cells, but not DC, have a unique ability to efficiently trans infect TNin vitro In contrast, both B cells and DC mediated HIV-1 trans infection of memory and activated CD4+ T cells. Moreover, we found that TN isolated from HIV-1-infected nonprogressors (NP) harbor significantly disproportionately lower levels of HIV-1 DNA than TN isolated from progressors. This is consistent with our previous finding that antigen-presenting cells (APC) derived from NP do not efficiently trans infect CD4+ T cells due to alterations in APC cholesterol metabolism and cell membrane lipid raft organization. These findings support that B cell-mediated trans infection of TN with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression.IMPORTANCE The latent human immunodeficiency virus type 1 (HIV-1) reservoir in persons on antiretroviral therapy (ART) represents a major barrier to a cure. Although most studies have focused on the HIV-1 reservoir in the memory T cell subset, replication-competent HIV-1 has been isolated from TN, and CCR5-tropic HIV-1 has been recovered from CCR5neg TN from ART-suppressed HIV-1-infected individuals. In this study, we showed that CCR5neg TN are efficiently trans infected with R5-tropic HIV-1 by B lymphocytes, but not by myeloid dendritic cells. Furthermore, we found that TN isolated from NP harbor no or significantly fewer copies of HIV-1 DNA than those from ART-suppressed progressors. These findings support that B cell-mediated trans infection of TN with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. Understanding the establishment and maintenance of the HIV-1 latent reservoir is fundamental for the design of effective treatments for viral eradication.

CCR5 is a potential therapeutic target for cancer.

INTRODUCTION: Chemokines and their cognate receptors play a major role in modulating inflammatory responses. Depending on their ligand binding, chemokine receptors can stimulate both immune activating and inhibitory signaling pathways. The CC chemokine receptor 5 (CCR5) promotes immune responses by recruiting immune cells to the sites of inflammation/tumor, and is involved in stimulating tumor cell proliferation, invasion and migration through various mechanisms. Moreover, CCR5 also contributes to an immune-suppressive tumor microenvironment by recruiting regulatory T cells and myeloid-derived suppressor cells facilitating tumor development and progression. In summary, cells expressing CCR5 modulate immune response and tumor progression. Expression of CCR5 is increased in various malignancies and associated with poor outcome. Experimental data show promising efficacy signals with CCR5 antagonists in preclinical tumor models. Therefore, CCR5 has been recognized as a potential therapeutic target for cancer. AREAS COVERED: In this review, we focus on the role of CCR5 in cancer progression and discuss its impact and potential as a therapeutic target for cancer. EXPERT OPINION: Beyond immune-checkpoint inhibitors, potentially synergistic immune-modulatory drugs such as CCR5 antagonists are a promising approach to enlarge our treatment armamentarium against cancer.

System Genetics Including Causal Inference Identify Immune Targets for Coronary Artery Disease and the Lifespan.

BACKGROUND: Randomized clinical trials indicate that the immune response plays a significant role in coronary artery disease (CAD), a disorder impacting the lifespan potential. However, the identification of targets critical to the immune response in atheroma is still hampered by a lack of solid inference. METHODS: Herein, we implemented a system genetics approach to identify causally associated immune targets implicated in atheroma. We leveraged genome-wide association studies to perform mapping and Mendelian randomization to assess causal associations between gene expression in blood cells with CAD and the lifespan. Expressed genes (eGenes) were prioritized in network and in single-cell expression derived from plaque immune cells. RESULTS: Among 840 CAD-associated blood eGenes, 37 were predicted causally associated with CAD and 6 were also associated with the parental lifespan in Mendelian randomization. In multivariable Mendelian randomization, the impact of eGenes on the lifespan potential was mediated by the CAD risk. Predicted causal eGenes were central in network. FLT1 and CCR5 were identified as targets of approved drugs, whereas 22 eGenes were deemed tractable for the development of small molecules and antibodies. Analyses of plaque immune single-cell expression identified predicted causal eGenes enriched in macrophages (GPX1, C4orf3) and involved in ligand-receptor interactions (CCR5). CONCLUSIONS: We identified 37 blood eGenes predicted causally associated with CAD. The predicted expression for 6 eGenes impacted the lifespan potential through the risk of CAD. Prioritization based on network, annotations, and single-cell expression identified targets deemed tractable for the development of drugs and for drug repurposing.

CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication.

BackgroundWe conducted a phase I clinical trial that infused CCR5 gene-edited CD4+ T cells to determine how these T cells can better enable HIV cure strategies.MethodsThe aim of trial was to develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene-edited CD4+ T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene-edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Δ32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4+ T cells, and whether infusion of 10 billion CCR5-edited CD4+ T cells augmented the HIV-specific immune response.ResultsInfusion of the CD4+ T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 Δ32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific CD8+ T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced CD8+ T cell responses.ConclusionThese findings demonstrate how CCR5 gene-edited CD4+ T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses.REGISTRATIONClinicalTrials.gov NCT02388594.FundingNIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies.