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Berlin Brandenburg

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  • 1
    In: Cell Research, 2013
    Description: CD4 super(+) T lymphocytes represent the main target cell population of human immunodeficiency virus (HIV). In an activated state, CD4 super(+) T cells residing in lymphoid organs are a major reservoir of ongoing HIV-1 replication in infected individuals. In contrast, resting CD4 super(+) T cells are highly resistant to productive HIV-1 infection, yet are massively depleted during disease progression and represent a substantial latent reservoir for the virus in vivo. Barriers preventing replication of HIV-1 in resting CD4 super(+) T cells include a rigid layer of cortical actin and, early after HIV-1 entry, a block that limits reverse transcription of incoming viral RNA genomes. Defining the molecular bases of these restrictions has remained one of the central open questions in HIV research. Recent advances unraveled mechanisms by which HIV-1 bypasses the entry block and established the host cell restriction factor SAMHD1, a deoxynucleoside triphosphate triphosphohydrolase, as a central determinant of the cellular restriction to HIV-1 reverse transcription in resting CD4 super(+) T cells. This review summarizes our current molecular and pathophysiological understanding of the multi-faceted interactions of HIV-1 with resting CD4 super(+) T lymphocytes.
    Keywords: Genomes ; Cd4 Antigen ; Cortex ; RNA ; Replication ; Lymphocytes T ; Actin ; Infection ; Reverse Transcription ; Human Immunodeficiency Virus 1 ; Microorganisms & Parasites ; AIDS and HIV;
    ISSN: 1001-0602
    E-ISSN: 17487838
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  • 2
    In: Nature Medicine, 2012, Vol.18(11), p.1682
    Description: Unlike activated CD4 super(+) T cells, resting CD4 super(+) T cells are highly resistant to productive HIV-1 infection. Early after HIV-1 entry, a major block limits reverse transcription of incoming viral genomes. Here we show that the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 prevents reverse transcription of HIV-1 RNA in resting CD4 super(+) T cells. SAMHD1 is abundantly expressed in resting CD4 super(+) T cells circulating in peripheral blood and residing in lymphoid organs. The early restriction to infection in unstimulated CD4 super(+) T cells is overcome by HIV-1 or HIV-2 virions into which viral Vpx is artificially or naturally packaged, respectively, or by addition of exogenous deoxynucleosides. Vpx-mediated proteasomal degradation of SAMHD1 and elevation of intracellular deoxynucleotide pools precede successful infection by Vpx-carrying HIV. Resting CD4 super(+) T cells from healthy donors following SAMHD1 silencing or from a patient with Aicardi-Goutieres syndrome homozygous for a nonsense mutation in SAMHD1 were permissive for HIV-1 infection. Thus, SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4 super(+) T cells in vivo. Bypassing SAMHD1 was insufficient for the release of viral progeny, implicating other barriers at later stages of HIV replication. Together, these findings may unveil new ways to interfere with the immune evasion and T cell immunopathology of pandemic HIV-1.
    Keywords: Virions ; Genomes ; Replication ; Proteasomes ; Peripheral Blood ; Infection ; Reverse Transcription ; Nonsense Mutation ; Cd4 Antigen ; Pandemics ; RNA ; Lymphocytes T ; Progeny ; Human Immunodeficiency Virus 1 ; Human Immunodeficiency Virus 2 ; Microorganisms & Parasites ; AIDS and HIV;
    ISSN: 1078-8956
    E-ISSN: 1546170X
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  • 3
    In: Nature Medicine, 2016
    Description: The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells1. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking2, 3. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate4, 5. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs6, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity--through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles7, 8--potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.
    Keywords: Leukemia ; Chemotherapy ; Biomarkers ; Medical Prognosis ; Cytotoxicity;
    ISSN: 1078-8956
    E-ISSN: 1546-170X
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  • 4
    In: Nature Medicine, 2017, Vol.23(6), p.788
    Description: Corrigendum: SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia
    Keywords: Medicine ; Biology;
    ISSN: 1078-8956
    E-ISSN: 1546-170X
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 March 2017, Vol.114(10), pp.2729-2734
    Description: Early after entry into monocytes, macrophages, dendritic cells, and resting CD4 T cells, HIV encounters a block, limiting reverse transcription (RT) of the incoming viral RNA genome. In this context, dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) has been identified as a restriction factor, lowering the concentration of dNTP substrates to limit RT. The accessory lentiviral protein X (Vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, sooty mangabey, and HIV-2 (SIVsmm/SIVmac/HIV-2) lineage packaged into virions target SAMHD1 for proteasomal degradation, increase intracellular dNTP pools, and facilitate HIV cDNA synthesis. We find that virion-packaged Vpx proteins from a second SIV lineage, SIV of red-capped mangabeys or mandrills (SIVrcm/mnd-2), increased HIV infection in resting CD4 T cells, but not in macrophages, and, unexpectedly, acted in the absence of SAMHD1 degradation, dNTP pool elevation, or changes in SAMHD1 phosphorylation. Vpx rcm/mnd-2 virion incorporation resulted in a dramatic increase of HIV-1 RT intermediates and viral cDNA in infected resting CD4 T cells. These analyses also revealed a barrier limiting HIV-1 infection of resting CD4 T cells at the level of nuclear import. Single amino acid changes in the SAMHD1-degrading Vpx mac239 allowed it to enhance early postentry steps in a Vpx rcm/mnd-2-like fashion. Moreover, Vpx enhanced HIV-1 infection of SAMHD1-deficient resting CD4 T cells of a patient with Aicardi-Goutières syndrome. These results indicate that Vpx, in addition to SAMHD1, overcomes a previously unappreciated restriction for lentiviruses at the level of RT that acts independently of dNTP concentrations and is specific to resting CD4 T cells.
    Keywords: HIV ; Samhd1 ; Vpx ; Resting Cd4 T Cells ; Restriction Factors ; HIV Infections -- Genetics ; Reverse Transcription -- Genetics ; SAM Domain and HD Domain-Containing Protein 1 -- Genetics ; Viral Regulatory and Accessory Proteins -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 6
    Language: English
    In: 2015, Vol.11(6), p.e1005005
    Description: DCs express intrinsic cellular defense mechanisms to specifically inhibit HIV-1 replication. Thus, DCs are productively infected only at very low levels with HIV-1, and this non-permissiveness of DCs is suggested to go along with viral evasion. We now illustrate that complement-opsonized HIV-1 (HIV-C) efficiently bypasses SAMHD1 restriction and productively infects DCs including BDCA-1 DCs. Efficient DC infection by HIV-C was also observed using single-cycle HIV-C, and correlated with a remarkable elevated SAMHD1 T592 phosphorylation but not SAMHD1 degradation. If SAMHD1 phosphorylation was blocked using a CDK2-inhibitor HIV-C-induced DC infection was also significantly abrogated. Additionally, we found a higher maturation and co-stimulatory potential, aberrant type I interferon expression and signaling as well as a stronger induction of cellular immune responses in HIV-C-treated DCs. Collectively, our data highlight a novel protective mechanism mediated by complement opsonization of HIV to effectively promote DC immune functions, which might be in the future exploited to tackle HIV infection. ; We here give insight into a substantial novel way of dendritic cell modulation at least during acute HIV-1 infection by triggering integrin receptor signaling. We found that complement-opsonization of the virus is able to relieve SAMHD1 restriction in DCs, thereby initiating strong maturation and co-stimulatory capacity of the cells and stimulating efficient cellular and humoral antiviral immune responses. This newly described way of DC modulation by complement might be exploited to find novel therapeutic targets promoting DC immune functions against HIV.
    Keywords: Research Article
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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  • 7
    In: Journal of Antimicrobial Chemotherapy, 2014, Vol. 69(10), pp.2809-2818
    Description: OBJECTIVES: The rapid early-phase decay of plasma HIV-1 RNA during integrase inhibitor-based therapy is not fully understood. The accumulation of biologically active episomal HIV-1 cDNAs, following aborted integration, could contribute to antiviral potency in vivo.METHODS: This prospective, controlled clinical observation study explored raltegravir's impact on the dynamics of HIV-1 RNA in plasma, and concentrations of total HIV-1 cDNA, episomal 2-long terminal repeat (LTR) circles and HIV-1 integrants in peripheral blood mononuclear cells (PBMC). Individuals starting therapy with two nucleoside reverse transcriptase inhibitors plus either raltegravir (raltegravir group; n = 10 patients) or boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitor (control group; n = 10 patients) were followed for 48 weeks.RESULTS: Suppression of HIV-1 RNA (〈50 copies/mL) was reached earlier (5/10 versus 0/10 at week 4; 8/10 versus 4/10 at week 12) on raltegravir. Significant total HIV-1 cDNA reductions in PBMC were reached by day 99 and persisted until day 330, with median factors of decrease of 7.2 and 8.9, respectively. Broad inter-individual variations, yet no treatment-associated differences, were noted for HIV-1 cDNA concentrations. Despite reductions in HIV-1 RNA (∼3 log) and total HIV-1 cDNA (∼1 log), concentrations of integrants and 2-LTR circles remained largely unchanged.CONCLUSIONS: These results extend the previously reported early benefit of raltegravir on the decline of plasma viraemia to treatment-naive patients. The modest treatment-associated, yet group-independent, decline in total HIV-1 cDNA load and the lack of significant changes in integrated and episomal HIV-1 cDNA suggest that most integrated DNA is archival and targeting of HIV reservoirs other than PBMC may underlie beneficial effects of raltegravir.
    Keywords: Virus Load ; Decay ; Slope ; Antiretroviral Therapy ; Integrase Inhibitor ; Viral Dynamics ; Episomal Dna ; 2 - Ltr Circles
    ISSN: 0305-7453
    E-ISSN: 1460-2091
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  • 8
    In: Journal of Leukocyte Biology, September 2016, Vol.100(3), pp.491-498
    Description: IL‐7 promotes regulatory T cell development in the human thymus by inhibiting apoptosis and enhancing emergence of the regulatory phenotype. Although mature human FOXP3 regulatory T cells are CD127 (IL‐7Rα) negative, CD4CD8 FOXP3 thymocytes express relatively high levels of CD127 and are responsive to IL‐7. However, the role of IL‐7 in human regulatory T cell development is poorly known. We show that at the CD4CD8 stage, FOXP3 thymocytes are highly susceptible to apoptosis, and IL‐7 selectively rescues them from death, leading to an increased frequency of FOXP3 cells. IL‐7 also promotes the development of regulatory T cell phenotype by inducing up‐regulation of FOXP3 and CTLA‐4 expression. In contrast, IL‐7 does not enhance proliferation of FOXP3thymocytes or induce demethylation of FOXP3 regulatory T cell‐specific demethylated region. After the CD4CD8 stage, the FOXP3 thymocytes down‐regulate CD127 expression but despite very low levels of CD127, remain responsive to IL‐7. These results suggest that IL‐7 affects human regulatory T cell development in the thymus by at least 2 distinct mechanisms: suppression of apoptosis and up‐regulation of FOXP3 expression.
    Keywords: Thymus ; Cytokines ; Apoptosis
    ISSN: 0741-5400
    E-ISSN: 1938-3673
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  • 9
    In: Schneider, Constanze and Oellerich, Thomas and Baldauf, Hanna-Mari and Schwarz, Sarah-Marie and Thomas, Dominique and Flick, Robert and Bohnenberger, Hanibal and Kaderali, Lars and Stegmann, Lena and Cremer, Anjali and Martin, Margarethe and Lohmeyer, Julian and Michaelis, Martin and Hornung, Veit and Schliemann, Christoph and Berdel, Wolfgang E and Hartmann, Wolfgang and Wardelmann, Eva and Comoglio, Federico and Hansmann, Martin-Leo and Yakunin, Alexander F and Geisslinger, Gerd and Ströbel, Philipp and Ferreirós, Nerea and Serve, Hubert and Keppler, Oliver T and Cinatl, Jindrich (2016) SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nature medicine, 23 (2). pp. 250-255.
    Description: The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.
    Keywords: RM Therapeutics. Pharmacology
    ISSN: 1078-8956
    Source: University of Kent
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  • 10
    Language: English
    In: Immunogenetics, 2016, Vol.68(6), pp.477-482
    Description: CD4 is the major receptor on T helper cells involved in the uptake of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) into their host cells. Evolutionary studies of CD4 in primates revealed signatures of positive selection in the D1 domain that interacts with primate exogenous lentivirus gp120 proteins. Here, we studied the evolution of CD4 in lagomorphs by comparing sequences obtained for the genera Oryctolagus , Sylvilagus , Lepus , and Ochotona . Our results reveal an overall higher divergence in lagomorphs compared to primates with highest divergence in the D2 domain. A detailed analysis of a small fragment of 33 nucleotides coding for amino acids 169 to 179 in the D2 domain showed dramatic amino acid alterations with a d N /d S value of 3.2 for lagomorphs, suggesting that CD4 is under strong positive selection in this particular region. Within each leporid genus, no significant amino acid changes were observed for the D2 domain which indicates that the genetic differentiation occurred in the ancestor of each genus before the species radiation. The rabbit endogenous lentivirus type K (RELIK) found in leporids shares high structural similarity with HIV which suggests a possible interaction between RELIK and CD4. The presence of RELIK in the studied leporids, the high structural similarity to modern-day exogenous lentiviruses and the absence of exogenous lentiviruses in leporids, allows us to hypothesize that this endogenous retrovirus, that was most probably exogenous in the past, drove the divergent evolution of leporid CD4.
    Keywords: CD4 ; Leporids ; Positive selection ; RELIK
    ISSN: 0093-7711
    E-ISSN: 1432-1211
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