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CXCR7/ACKR3-targeting ligands interfere with X7 HIV-1 and HIV-2 entry and replication in human host cells.

ABSTRACT: Chemokine receptors CCR5 and CXCR4 are considered the main coreceptors for initial HIV infection, replication and transmission, and subsequent AIDS progression. Over the years, other chemokine receptors, belonging to the family of G protein-coupled receptors, have also been identified as candidate coreceptors for HIV entry into human host cells. Amongst them, CXCR7, also known as atypical chemokine receptor 3 (ACKR3), was suggested as a coreceptor candidate capable of facilitating both HIV-1 and HIV-2 entry in vitro. In this study, a cellular infection model was established to further decipher the role of CXCR7 as an HIV coreceptor. Using this model, CXCR7-mediated viral entry was demonstrated for several clinical HIV isolates as well as laboratory strains. Of interest, the X4-tropic HIV-1 HE strain showed rapid adaptation towards CXCR7-mediated infection after continuous passaging on CD4- and CXCR7-expressing cells. Furthermore, we uncovered anti-CXCR7 monoclonal antibodies, small molecule CXCR7 inhibitors and the natural CXCR7 chemokine ligands as potent inhibitors of CXCR7 receptor-mediated HIV entry and replication. Even though the clinical relevance of CXCR7-mediated HIV infection remains poorly understood, our data suggest that divergent HIV-1 and HIV-2 strains can quickly adapt their coreceptor usage depending on the cellular environment, which warrants further investigation.

SUBMITTER: D'huys T

PROVIDER: S-EPMC5857896 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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CXCR7/ACKR3-targeting ligands interfere with X7 HIV-1 and HIV-2 entry and replication in human host cells.

D'huys Thomas T Claes Sandra S Van Loy Tom T Schols Dominique D

Heliyon 20180301 3

Chemokine receptors CCR5 and CXCR4 are considered the main coreceptors for initial HIV infection, replication and transmission, and subsequent AIDS progression. Over the years, other chemokine receptors, belonging to the family of G protein-coupled receptors, have also been identified as candidate coreceptors for HIV entry into human host cells. Amongst them, CXCR7, also known as atypical chemokine receptor 3 (ACKR3), was suggested as a coreceptor candidate capable of facilitating both HIV-1 and ...[more]

PMID: 29560468

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Project description:UnlabelledThe atypical chemokine receptor ACKR3 (formerly CXCR7), overexpressed in various cancers compared with normal tissues, plays a pivotal role in adhesion, angiogenesis, tumorigenesis, metastasis, and tumor cell survival. ACKR3 modulates the tumor microenvironment and regulates tumor growth. The therapeutic potential of ACKR3 has also been demonstrated in various murine models of human cancer. Literature findings underscore the importance of ACKR3 in disease progression and suggest it as an important diagnostic marker for noninvasive imaging of ACKR3-overexpressing malignancies. There are currently no reports on direct receptor-specific detection of ACKR3 expression. Here we report the evaluation of a radiolabeled ACKR3-targeted monoclonal antibody (ACKR3-mAb) for the noninvasive in vivo nuclear imaging of ACKR3 expression in human breast, lung, and esophageal squamous cell carcinoma cancer xenografts.MethodsACKR3 expression data were extracted from Cancer Cell Line Encyclopedia, The Cancer Genome Atlas, and the Clinical Lung Cancer Genome Project. (89)Zr-ACKR3-mAb was evaluated in vitro and subsequently in vivo by PET and ex vivo biodistribution studies in mice xenografted with breast (MDA-MB-231-ACKR3 [231-ACKR3], MDA-MB-231 [231], MCF7), lung (HCC95), or esophageal (KYSE520) cancer cells. In addition, ACKR3-mAb was radiolabeled with (125)I and evaluated by SPECT imaging and ex vivo biodistribution studies.ResultsACKR3 transcript levels were highest in lung squamous cell carcinoma among the 21 cancer type data extracted from The Cancer Genome Atlas. Also, Clinical Lung Cancer Genome Project data showed that lung squamous cell carcinoma had the highest CXCR7 transcript levels compared with other lung cancer subtypes. The (89)Zr-ACKR3-mAb was produced in 80% ± 5% radiochemical yields with greater than 98% radiochemical purity. In vitro cell uptake of (89)Zr-ACKR3-mAb correlated with gradient levels of cell surface ACKR3 expression observed by flow cytometry. In vivo PET imaging and ex vivo biodistribution studies in mice with breast, lung, and esophageal cancer xenografts consistently showed enhanced (89)Zr-ACKR3-mAb uptake in high-ACKR3-expressing tumors. SPECT imaging of (125)I-ACKR3-mAb showed the versatility of ACKR3-mAb for in vivo monitoring of ACKR3 expression.ConclusionData from this study suggest ACKR3 to be a viable diagnostic marker and demonstrate the utility of radiolabeled ACKR3-mAb for in vivo visualization of ACKR3-overexpressing malignancies.

Project description:We found earlier that ectopic expression of the cytidine deaminase APOBEC3G (A3G) in Vero cells inhibits measles virus (MV), respiratory syncytial virus, and mumps virus, while the mechanism of inhibition remained unclear. A microarray analysis revealed that in A3G-transduced Vero cells, several cellular transcripts were differentially expressed, suggesting that A3G regulates the expression of host factors. One of the most upregulated host cell factors, REDD1 (regulated in development and DNA damage response-1, also called DDIT4), reduced MV replication ∼10-fold upon overexpression in Vero cells. REDD1 is an endogenous inhibitor of mTORC1 (mammalian target of rapamycin complex-1), the central regulator of cellular metabolism. Interestingly, rapamycin reduced the MV replication similarly to REDD1 overexpression, while the combination of both did not lead to further inhibition, suggesting that the same pathway is affected. REDD1 silencing in A3G-expressing Vero cells abolished the inhibitory effect of A3G. In addition, silencing of A3G led to reduced REDD1 expression, confirming that its expression is regulated by A3G. In primary human peripheral blood lymphocytes (PBL), expression of A3G and REDD1 was found to be stimulated by phytohemagglutinin (PHA) and interleukin-2. Small interfering RNA (siRNA)-mediated depletion of A3G in PHA-stimulated PBL reduced REDD1 expression and increased viral titers, which corroborates our findings in Vero cells. Silencing of REDD1 also increased viral titers, confirming the antiviral role of REDD1. Finally, pharmacological inhibition of mTORC1 by rapamycin in PHA-stimulated PBL reduced viral replication to the level found in unstimulated lymphocytes, indicating that mTORC1 activity supports MV replication as a proviral host factor.IMPORTANCE Knowledge about host factors supporting or restricting virus replication is required for a deeper understanding of virus-cell interactions and may eventually provide the basis for therapeutic intervention. This work was undertaken predominantly to explain the mechanism of A3G-mediated inhibition of MV, a negative-strand RNA virus that is not affected by the deaminase activity of A3G acting on single-stranded DNA. We found that A3G regulates the expression of several cellular proteins, which influences the capacity of the host cell to replicate MV. One of these, REDD1, which modulates the cellular metabolism in a central position by regulating the kinase complex mTORC1, was identified as the major cellular factor impairing MV replication. These findings show interesting aspects of the function of A3G and the dependence of the MV replication on the metabolic state of the cell. Interestingly, pharmacological inhibition of mTORC1 can be utilized to inhibit MV replication in Vero cells and primary human peripheral blood lymphocytes.

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CXCR7/ACKR3-targeting ligands interfere with X7 HIV-1 and HIV-2 entry and replication in human host cells.

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CXCR7/ACKR3-targeting ligands interfere with X7 HIV-1 and HIV-2 entry and replication in human host cells.

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