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Zirafi O.,Institute of Molecular Virology | Munch J.,Institute of Molecular Virology | Munch J.,University of Ulm
Journal of Leukocyte Biology | Year: 2016

The chemokine receptor CXCR4 is an important G protein-coupled receptor. Signaling via CXCL12 regulates a number of important biologic processes, including immune responses, organogenesis, or hematopoiesis. Dysregulation of CXCR4 signaling is associated with a variety of diseases, such as cancer development and metastasis, immunodeficiencies, or chronic inflammation. Here, we review our findings on endogenous peptide inhibitor of CXCR4 as a novel antagonist of CXCR4. This peptide is a 16-residue fragment of human serum albumin and was isolated as an inhibitor of CXCR4-tropic human immunodeficiency virus type 1 from a blood-derived peptide library. Endogenous peptide inhibitor of CXCR4 binds the second extracellular loop of CXCR4, thereby preventing engagement of CXCL12 and antagonizing the receptor. Consequently, endogenous peptide inhibitor of CXCR4 inhibits CXCL12-mediated migration of CXCR4-expressing cells in vitro, mobilizes hematopoietic stem cells, and suppresses inflammatory responses in vivo. We discuss the generation of endogenous peptide inhibitor of CXCR4, its relevance as biomarker for disease, and its role in human immunodeficiency virus/acquired immunodeficiency syndrome pathogenesis and cancer. Furthermore, we discuss why optimized endogenous peptide inhibitor of CXCR4 derivatives might have advantages over other CXCR4 antagonists. © Society for Leukocyte Biology. Source


Roan N.R.,Gladstone | Muller J.A.,Institute of Molecular Virology | Liu H.,University of California at San Francisco | Chu S.,Gladstone | And 9 more authors.
Cell Host and Microbe | Year: 2011

Semen serves as a vehicle for HIV and promotes sexual transmission of the virus, which accounts for the majority of new HIV cases. The major component of semen is the coagulum, a viscous structure composed predominantly of spermatozoa and semenogelin proteins. Due to the activity of the semen protease PSA, the coagulum is liquefied and semenogelins are cleaved into smaller fragments. Here, we report that a subset of these semenogelin fragments form amyloid fibrils that greatly enhance HIV infection. Like SEVI, another amyloid fibril previously identified in semen, the semenogelin fibrils exhibit a cationic surface and enhance HIV virion attachment and entry. Whereas semen samples from healthy individuals greatly enhance HIV infection, semenogelin-deficient semen samples from patients with ejaculatory duct obstruction are completely deficient in enhancing activity. Semen thus harbors distinct amyloidogenic peptides derived from different precursor proteins that commonly enhance HIV infection and likely contribute to HIV transmission. © 2011 Elsevier Inc. Source


Dudek S.E.,Institute of Molecular Virology | Dudek S.E.,ViroLogik GmbH | Luig C.,Institute of Molecular Virology | Pauli E.-K.,ViroLogik GmbH | And 2 more authors.
Journal of Virology | Year: 2010

Recently it has been shown that the proinflammatory NF-κB pathway promotes efficient influenza virus propagation. Based on these findings, it was suggested that NF-κB blockade may be a promising approach for antiviral intervention. The classical virus-induced activation of the NF-κB pathway requires proteasomal degradation of the inhibitor of NF-κB, IκB. Therefore, we hypothesized that inhibition of proteasomal IκB degradation should impair influenza A virus (IAV) replication. We chose the specific proteasome inhibitor PS-341, which is a clinically approved anticancer drug also known as Bortezomib or Velcade. As expected, PS-341 treatment of infected A549 cells in a concentration range that was not toxic resulted in a significant reduction of progeny virus titers. However, we could not observe the proposed suppression of NF-κB-signaling in vitro. Rather, PS-341 treatment resulted in an induction of IκB degradation and activation of NF-κB as well as the JNK/AP-1 pathway. This coincides with enhanced expression of antiviral genes, such as interleukin-6 and, most importantly, MxA, which is a strong interferon (IFN)-induced suppressor of influenza virus replication. This suggests that PS-341 may act as an antiviral agent via induction of the type I IFN response. Accordingly, PS-341 did not affect virus titers in Vero cells, which lack type I IFN genes, but strongly inhibited replication of vesicular stomatitis virus (VSV), a highly IFN-sensitive pathogen. Thus, we conclude that PS-341 blocks IAV and VSV replication by inducing an antiviral state mediated by the NF-κB-dependent expression of antivirus-acting gene products. Copyright © 2010, American Society for Microbiology. All Rights Reserved. Source


Lackey L.,Institute of Molecular Virology | Lackey L.,University of Minnesota | Law E.K.,Institute of Molecular Virology | Law E.K.,University of Minnesota | And 4 more authors.
Cell Cycle | Year: 2013

Humans have seven APO BEC3 DNA cytosine deaminases. The activity of these enzymes allows them to restrict a variety of retroviruses and retrotransposons, but may also cause pro-mutagenic genomic uracil lesions. During interphase the APO BEC3 proteins have different subcellular localizations: cell-wide, cytoplasmic or nuclear. This implies that only a subset of APO BEC3s have contact with nuclear DNA. However, during mitosis, the nuclear envelope breaks down and cytoplasmic proteins may enter what was formerly a privileged zone. To address the hypothesis that all APO BEC3 proteins have access to genomic DNA, we analyzed the localization of the APO BEC3 proteins during mitosis. We show that APO BEC3A, APO BEC3C and APO BEC3H are excluded from condensed chromosomes, but become cell-wide during telophase. However, APO BEC3B, APO BEC3D, APO BEC3F and APO BEC3G are excluded from chromatin throughout mitosis. After mitosis, APO BEC3B becomes nuclear, and APO BEC3D, APO BEC3F and APO BEC3G become cytoplasmic. Both structural motifs as well as size may be factors in regulating chromatin exclusion. Deaminase activity was not dependent on cell cycle phase. We also analyzed APO BEC3-induced cell cycle perturbations as a measure of each enzyme's capacity to inflict genomic DNA damage. AID, APO BEC3A and APO BEC3B altered the cell cycle profile, and, unexpectedly, APO BEC3D also caused changes. We conclude that several APO BEC3 family members have access to the nuclear compartment and can impede the cell cycle, most likely through DNA deamination and the ensuing DNA damage response. Such genomic damage may contribute to carcinogenesis, as demonstrated by AID in B cell cancers and, recently, APO BEC3B in breast cancers. Copyright © 2013 Landes Bioscience. Source

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