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January 2009 - present
January 2005 - December 2009
January 2003 - present
Publications
Publications (158)
The rather few cases of humans infected by HIV-1 N, O, or P raise the question of their incomplete adaptation to humans. We hypothesized that early postentry restrictions may be relevant for the impaired spread of these HIVs. One of the best-characterized species-specific restriction factors is TRIM5α. HIV-1 M can escape human (hu) TRIM5α restricti...
Sensing of human immunodeficiency virus type 1 (HIV-1) DNA is mediated by the cyclic GMP-AMP synthasestimulator
of interferon genes (cGAS-STING) signaling axis. Signal transduction and regulation of this cascade
is achieved by post-translational modifications. Here we show that cGAS-STING-dependent HIV-1 sensing
requires interferon-stimulated gene...
Despite scientific evidence originating from two patients published to date that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterize a case of long-term HIV-1 remission of a 53-year-old male...
Human immunodeficiency virus-1 (HIV-1) is a retrovirus that integrates its reverse-transcribed genome as proviral DNA into the host genome to establish a successful infection. The viral genome integration requires safeguarding the subviral complexes, reverse transcription complex (RTC) and preintegration complex (PIC), in the cytosol from degradati...
The tumor microenvironment (TM), consisting of the extracellular matrix (ECM), fibroblasts, endothelial cells and immune cells, might affect tumor invasiveness and the outcome of standard chemotherapy. This study investigated the cross‐talk between germ cell tumors (GCT) and surrounding TM cells (macrophages, T‐lymphocytes, endothelial cells, fibro...
Nucleocytoplasmic shuttling of viral elements, supported by several host factors, is essential for the replication of the Human Immunodeficiency Virus (HIV). HIV‐1 uses a nuclear RNA export pathway mediated by viral protein Rev to transport its Rev Response Element (RRE)‐containing partially spliced and unspliced transcripts aided by the host nucle...
Serine incorporator 5 (SERINC5 or SER5) is a multipass transmembrane protein with ill-defined cellular activities. SER5 was recently described as a human immunodeficiency virus 1 (HIV-1) restriction factor capable of inhibiting HIV-1 that does not express its accessory protein Nef (Δ Nef). SER5 incorporated into the viral membrane impairs the entry...
Major histocompatibility complex I (MHC‐I) molecules present epitopes on the cellular surface of antigen‐presenting cells to prime cytotoxic clusters of differentiation 8 (CD8)+ T cells (CTLs), which then identify and eliminate other cells such as virus‐infected cells bearing the antigen. Human hepatitis virus cohort studies have previously identif...
Staufen, the RNA-binding family of proteins, affects various steps in the Human Immuno-Deficiency Virus (HIV-1) replication cycle. While our previous study established Staufen-2–HIV-1 Rev interaction and its role in augmenting nucleocytoplasmic export of RRE-containing viral RNA, viral incorporation of Staufen-2 and its effect on viral propagation...
Human SERINC5 (SER5) protein is a recently described restriction factor against human immunodeficiency virus-1 (HIV-1), which is antagonized by HIV-1 Nef protein. Other retroviral accessory proteins such as the glycosylated Gag (glycoGag) from the murine leukemia virus (MLV) can also antagonize SER5. In addition, some viruses escape SER5 restrictio...
Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could pote...
In this Special Issue, a wide variety of original and review articles provide a time-ly overview of how viruses are recognized by and evade from cellular innate immuni-ty, which represents the first line of defense against viruses [...]
Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic potential are occasionally detected in bushmeat hunters or zook...
The human APOBEC3A (A3A) polynucleotide cytidine deaminase has been shown to have antiviral activity against HTLV-1 but not HIV-1, when expressed in the virus producer cell. In viral target cells, high levels of endogenous A3A activity have been associated with the restriction of HIV-1 during infection. Here we demonstrate that A3A derived from bot...
The family of human APOBEC3 (A3) restriction factors is formed by seven different proteins, A3A–D and A3F–H. Among these A3s, A3B harbors strong restriction activity against several retroviruses, such as SIV, and MLV. How lentiviruses and other retroviruses, prevalent in many primate species, counteract A3B is poorly understood.
In this study, we...
APOBEC3 deaminases (A3s) provide mammals with an anti-retroviral barrier by catalyzing dC-to-dU deamination on viral ssDNA. Within primates, A3s have undergone a complex evolution via gene duplications, fusions, arms race and selection. Human APOBEC3C (hA3C) efficiently restricts the replication of viral infectivity factor (vif)-deficient Simian im...
Pandemic human immunodeficiency virus type 1 (HIV-1) is the result of the zoonotic transmission of simian immunodeficiency virus (SIV) from the chimpanzee subspecies Pan troglodytes troglodytes (SIVcpzPtt). The related subspecies Pan troglodytes schweinfurthii is the host of a similar virus, SIVcpzPts, which did not spread to humans. We tested thes...
Macrophages and dendritic cells dominate early immune responses to lentiviruses. HIV-1 sensing by pathogen recognition receptors induces signaling cascades that culminate in type I alpha/beta interferon (IFN-α/β) induction. IFN-α/β signals back via the IFN-α/β receptors, inducing a plethora of IFN-stimulated gene (ISGs), including ISG15, p53, and p...
Macrophages and dendritic cells dominate early immune responses to lentiviruses. HIV-1 sensing by pathogen recognition receptors induces signaling cascades that culminate in type I alpha/beta interferon (IFN-/) induction. IFN-/ signals back via the IFN-/ receptors, inducing a plethora of IFN-stimulated gene (ISGs), including ISG15, p53, and p21 Cip...
Background:
Hosts are able to restrict viral replication to contain virus spread before adaptive immunity is fully initiated. Many viruses have acquired genes directly counteracting intrinsic restriction mechanisms. This phenomenon has led to a co-evolutionary signature for both the virus and host which often provides a barrier against interspecie...
Pandemic HIV-1, a human lentivirus, is the result of zoonotic transmission of SIV from chimpanzees
(SIVcpz). How SIVcpz established spread in humans after spillover is an outstanding question. Lentiviral
cross-species transmissions are exceptionally rare events. Nevertheless, the chimpanzee and the gorilla
were part of the transmission chains that...
https://www.journals.elsevier.com/virology/blog-archive/human-mxb-aka-mx2-a-new-host-factor-to-limit-herpesvirus
The MX dynamin GTPases inhibit diverse viruses at early post-entry phases. While MXA acts antiviral against influenza viruses, the anti HIV-1 activity of MXB was discovered recently. Here, we have studied the antiviral effect of MX proteins on murine cytomegalovirus (MCMV). Our data demonstrate that human MXB but not other
human or murine MX protei...
The most common mutational signature in urinary bladder urothelial carcinoma (UC) is assumed to be caused by the misdirected activity of APOBEC3 (A3) cytidine deaminases, especially A3A or A3B, which are known to normally restrict the propagation of exogenous viruses and endogenous retroelements such as LINE-1 (L1). The involvement of A3 proteins i...
Macrophages and dendritic cells are usually the first point of contact with pathogens, including lentiviruses. Host restriction factors, including SAMHD1, mediate the innate immune response against these viruses. However, HIV-1 has evolved to circumvent the innate immune response and establishes disseminated infection. The cyclin-dependent kinase i...
The replication of lentiviruses highly depends on host cellular factors, which defines their species-specific tropism. Cellular restriction factors that can inhibit lentiviral replication were recently identified. Feline immunodeficiency virus (FIV) was found to be sensitive to several feline cellular restriction factors, such as apolipoprotein B m...
Successful replication of Human immunodeficiency virus (HIV)-1 depends on the expression of various cellular host factors, such as the interleukin-2 inducible T-cell kinase (ITK), a member of the protein family of TEC-tyrosine kinases. ITK is selectively expressed in T-cells and coordinates signaling pathways downstream of the T-cell receptor and c...
Members of the APOBEC3 (A3) family of enzymes were shown to act in an oncogenic manner in several cancer types. Immunodetection of APOBEC3A (A3A), APOBEC3B (A3B), and APOBEC3G (A3G) proteins is particularly challenging due to the large sequence homology of these proteins and limited availability of antibodies. Here we combine independent immunoblot...
Author summary
Cellular cytidine deaminases of the APOBEC3 (A3) family are potent restriction factors that are able to inhibit retroviruses, this A3 restriction is counteracted by lentivirus Vif proteins. Human APOBEC3H (A3H) represents the most evolutionarily divergent A3 gene; it includes seven haplotypes and several splice variants. The polymorp...
(a) Characterization of SupT11-vetor-hCCR5 or SupT11-hA3H hapII-hCCR5 cells for expression of hA3H hapII using immunoblots of cell lysates and anti-hA3H antibody. Tubulin served as a loading control and (b) for expression of CCR5 and CD4 by flow cytometry. Cells were stained by α-hCCR5 FITC, or α-hCD4 PE mouse IgG1k separately. The mouse IgG1/RPE i...
Schematic genome structure of SIVcpzPttMB897 and SIVcpzPtsTAN1.
The restriction sites used for construction of nanoluciferase (NLuc) reporter viruses are shown. Stop codons were inserted in vif at positions for coding of amino acid 40 and 44.
(TIF)
Detection of A3 expression by immunoblots (a, b, c): 293T cells were transfected with 30 ng hA3s or 200 ng cpzA3s expression plasmids. Two days post-transfection, cell lysates were used to detect the expression of A3s by two different anti-HA antibodies. Tubulin served as a loading control. (d) SIVcpzPttMB897 or SIVcpzPtsTAN1 wild type or delta vif...
Structural superimposition of cpzA3H (a) The recent crystal structure of hA3H hapII (6B0B) was used to model the structure of cpzA3H. The SNPs of cpzA3H identified in this study were shown. (b) The potential SIVcpz/HIV-1 Vif interaction sites in helix-3 and helix-4 of cpzA3H (green) are shown.
(TIF)
The apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC3, A3) family of DNA cytidine deaminases are intrinsic restriction factors against retroviruses. In felids such as the domestic cat (Felis catus), the APOBEC3 (A3) genes encode for the A3Z2s, A3Z3, and A3Z2Z3 antiviral cytidine deaminases. Only A3Z3 and A3Z2Z3 inhibit viral...
The retroviral restriction factors of the APOBEC3 (A3) cytidine deaminase family catalyze the deamination of cytidines in single-stranded viral DNA. APOBEC3C (A3C) is a strong antiviral factor against viral infectivity factor (vif)-deficient simian immunodeficiency (SIV) Δvif, however, a weak inhibitor against human immunodeficiency virus (HIV)-1 f...
Importance:
Both human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV) Vif proteins counteract their host's APOBEC3 restriction factors. However, these two Vif proteins have limited sequence homology. The molecular interaction between FIV Vif and feline APOBEC3s are not well understood. Here we have identified N-terminal FIV V...
Importance:
The APOBEC3 restriction factors can serve as potential barriers to lentiviral cross-species transmissions. Vif proteins from lentiviruses counteract APOBEC3 by proteasomal degradation. In this study, we found that monkey-derived APOBEC3C (A3C), rhA3C and smmA3C were resistant to HIV-1 Vif. This was determined by A3C residues N/H130 and...
Background:
Feline immunodeficiency virus (FIV) is a global pathogen of Felidae species and a model system for Human immunodeficiency virus (HIV)-induced AIDS. In felids such as the domestic cat (Felis catus), APOBEC3 (A3) genes encode for single-domain A3Z2s, A3Z3 and double-domain A3Z2Z3 anti-viral cytidine deaminases. The feline A3Z2Z3 is expre...
APOBEC4 (A4) is a member of the AID/APOBEC family of cytidine deaminases. In this study we found a high mRNA expression of A4 in human testis. In contrast, there were only low levels of A4 mRNA detectable in 293T, HeLa, Jurkat or A3.01 cells. Ectopic expression of A4 in HeLa cells resulted in mostly cytoplasmic localization of the protein. To test...
Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) are not commonly used in clinical practice for treatment of B‐cell lymphomas, although a subset of patients with refractory or relapsed B‐cell lymphoma achieved partial or complete remissions.
Therefore, the purpose of this study was to identify molecular features...
Deoxynucleotide triphosphates (dNTPs) are essential for efficient hepatitis B virus (HBV) replication. Here, we investigated the influence of the restriction factor SAMHD1, a dNTP hydrolase (dNTPase) and RNase, on HBV replication. We demonstrated that silencing of SAMHD1 in hepatic cells increased HBV replication, while overexpression had the oppos...
Foamy viruses (FV) are retroviruses that are widely distributed in primate and non-primate animal species. We tested here FV with capsids of simian and non-simian origin for sensitivity to interferon-β (IFN-β). Our data show significant inhibition of FV by IFN-β early in infection of human HOS and THP-1 but not of HEK293T cells. The post-entry rest...
Nucleophosmin (NPM1, also known as B23, numatrin or NO38) is a pentameric RNA-binding protein with RNA and protein chaperon functions. NPM1 has increasingly emerged as a potential cellular factor that directly associates with viral proteins; however, the significance of these interactions in each case is still not clear. In this study, we have inve...
Analytical ultracentrifugation for the determination of the oligomeric state and molecular mass of US11 and NPM1.
(A) Sedimentation velocity analysis of US11FL and NPM1FL at 35,000 rpm and 20°C. Graphs show the evaluated c(s) distributions obtained by SEDFIT. For presentation, curves had been normalized to maximum peak height. Results revealed that...
Physical interaction of HIV-1 Rev with NPM1.
Quantitative interaction analysis were performed by ITC at 25°C by titrating (A) NPM1OD (450 μM) to 30 μM HIV-1 Rev, (B) NPM1HBD (350 μM) to 25 μM HIV-1 Rev and (C) NPM1HRBD (800 μM) to 50 μM HIV-1 Rev, respectively. The upper graph shows calorimetric changes plotted versus the time, and the lower graph...
The protease ADAM17 (a disintegrin and metalloproteinase 17) catalyzes the shedding of various
transmembrane proteins from the surface of cells, including tumor necrosis factor (TNF) and its receptors.
Liberation of TNF receptors (TNFRs) from cell surfaces can dampen the cellular response to TNF,
a cytokine that is critical in the innate immune res...
The protease ADAM17 (a disintegrin and metalloproteinase 17) catalyzes the shedding of various transmembrane proteins from the surface of cells, including tumor necrosis factor (TNF) and its receptors. Liberation of TNF receptors (TNFRs) from cell surfaces can dampen the cellular response to TNF, a cytokine that is critical in the innate immune res...
Importance:
Gene diversity and selective pressure are intriguing topics in the field of evolutionary biology. A direct interaction between a cellular protein and a viral protein can precipitate an evolutionary arms race between host and virus. One example is primate APOBEC3G, which potently restricts the replication of primate lentiviruses (e.g.,...
Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins are cellular DNA deaminases that restrict a broad spectrum of lentiviruses. This process is counteracted by the viral infectivity factor (Vif) of lentiviruses, which binds APOBEC3s and promotes their degradation. Core binding factor subunit β (CBF-β) is an essentia...
Background:
The HIV-1 accessory proteins, Viral Infectivity Factor (Vif) and the pleiotropic Viral Protein R (Vpr) are important for efficient virus replication. While in non-permissive cells an appropriate amount of Vif is critical to counteract APOBEC3G-mediated host restriction, the Vpr-induced G2 arrest sets the stage for highest transcription...
Clearance of Chronic Virus
The family of mRNA-editing enzymes, APOBEC, restricts hepatitis B virus (HBV) replication. Lucifora et al. (p. 1221 , published online 20 February; see the Perspective by Shlomai and Rice ) provide evidence that specific APOBECs mediate the anti-HBV effects of host cytokines, which in turn apparently induce nuclear deamin...
Human APOBEC3 (A3) cytosine deaminases are antiviral restriction factors capable of editing the genome the hepatitis B virus (HBV). Despite the importance of the human A3 protein family for the innate immune response little is known about the clinical relevance for hepatitis B. The aim of this study was to utilize ultra-deep pyrosequencing (UDPS) d...
LINE-1 (L1) retrotransposons are mobile genetic elements whose extensive proliferation resulted in the generation of ∼34% of the human genome. They have been shown to be a cause of single-gene diseases. Moreover, L1-encoded endonuclease can elicit double-strand breaks that may lead to genomic instability. Mammalian cells adopted strategies restrict...
APOBEC3 (A3) proteins restrict viral replication by cytidine deamination of viral DNA genomes and impairing reverse transcription and integration. To escape this restriction, lentiviruses have evolved the viral infectivity factor (Vif), which binds A3 proteins and targets them for proteolytic degradation. In contrast, foamy viruses (FVs) encode Bet...
Abstract The APOBEC3 (A3) family of cytidine deaminases plays a vital role for innate defence against retroviruses. Lentiviruses such as HIV-1 evolved the Vif protein that triggers A3 protein degradation. There are seven A3 proteins, A3A - A3H, found in humans. All A3 proteins can deaminate cytidines to uridines in single-stranded DNA (ssDNA), gene...
Cellular cytidine deaminases from the APOBEC3 family are potent restriction factors able to block the replication of retroviruses. Consequently, retroviruses have evolved a variety of different mechanisms to counteract inhibition by APOBEC3 proteins. Lentiviruses such as Human immunodeficiency virus (HIV) express Vif that interferes with APOBEC3 pr...
Within target T lymphocytes, human immunodeficiency virus type I (HIV-1) encounters the retroviral restriction factor APOBEC3G
(apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G; A3G), which is counteracted by the HIV-1 accessory protein
Vif. Vif is encoded by intron-containing viral RNAs that are generated by splicing at 3′ splic...
Human immunodeficiency virus-1 (HIV-1) dynamics reflect an intricate balance within the viruses’ host. The virus relies on host replication factors, but must escape or counter its host’s antiviral restriction factors. The interaction between the HIV-1 protein Vif and many cellular restriction factors from the APOBEC3 protein family is a prominent e...
