scholarly journals Immediate Activation Fails To Rescue Efficient Human Immunodeficiency Virus Replication in Quiescent CD4+ T Cells

2007 ◽  
Vol 81 (7) ◽  
pp. 3574-3582 ◽  
Author(s):  
Dimitrios N. Vatakis ◽  
Gregory Bristol ◽  
Thomas A. Wilkinson ◽  
Samson A. Chow ◽  
Jerome A. Zack
Keyword(s):  
Cell Cycle ◽  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Life Cycle ◽  
Viral Entry ◽  
Viral Protein ◽  
Brdu Incorporation ◽  
Human Immunodeficiency Virus Replication ◽  
Activated T Cells ◽  
Immunodeficiency Virus

ABSTRACT Unlike activated T cells, quiescent CD4+ T cells have shown resistance to human immunodeficiency virus (HIV) infection due to a block in the early events of the viral life cycle. To further investigate the nature of this block, we infected quiescent CD4+ T cells with HIV-1NL4-3 and immediately stimulated them. Compared to activated (prestimulated) cells, these poststimulated cells showed slightly decreased viral entry and delays in the completion of reverse transcription. However, the relative efficiency of integration was similar to that of prestimulated cells. Together, this resulted in decreased expression of tat/rev mRNA and synthesis of viral protein. Furthermore, based on cell cycle staining and BrdU incorporation, poststimulated cells expressing viral protein failed to initiate a second round of their cell cycle, independently of Vpr-mediated arrest. Together, these data demonstrate that the early stages of the HIV life cycle are inefficient in these poststimulated cells and that efficient replication cannot be induced by subsequent activation.

scholarly journals Modalities of Interleukin-7-Induced Human Immunodeficiency Virus Permissiveness in Quiescent T Lymphocytes

2002 ◽  
Vol 76 (18) ◽  
pp. 9103-9111 ◽  
Author(s):  
Odile Ducrey-Rundquist ◽  
Mireille Guyader ◽  
Didier Trono
Keyword(s):  
Cell Cycle ◽  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Lymphocytes ◽  
T Cell Homeostasis ◽  
Activated T Cells ◽  
Hiv Susceptibility ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Cell Cycle Status

ABSTRACT The metabolic and cell cycle status of primary T lymphocytes conditions their susceptibility to human immunodeficiency virus (HIV) and HIV-derived vectors. While in fully quiescent T lymphocytes the reverse transcription and nuclear import of these retroelements are impaired, leading to an abortive infection, various stimuli can induce a state of virus permissiveness. Here, we studied the modalities by which interleukin-7 (IL-7), an important controller of T-cell homeostasis, exerts this effect. IL-7-exposed cord blood T lymphocytes proliferated and were efficiently transduced by HIV-derived vectors. In contrast, similarly treated adult peripheral blood (PB) T lymphocytes failed to divide, and only a subset of these cells became infectible. HIV-resistant and -sensitive subsets of IL-7-treated PB T lymphocytes differed in cell cycle status but not in naïve, memory, or activation phenotypes. Nuclear factor of activated T cells was not induced by IL-7, and cyclosporine did not prevent HIV-mediated gene transfer. Furthermore, the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin blocked IL-7-induced cell survival and Bcl-2 synthesis but had no effect on the acquisition of HIV susceptibility, suggesting that IL-7-induced HIV type 1 permissiveness is not mediated by the PI-3 K pathway and that, perhaps, the Jak/STAT5 pathway, the other known mediator of IL-7-triggered signaling in T cells, governs this process.

scholarly journals Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist

2004 ◽  
Vol 78 (23) ◽  
pp. 12996-13006 ◽  
Author(s):  
Katrien Princen ◽  
Sigrid Hatse ◽  
Kurt Vermeire ◽  
Stefano Aquaro ◽  
Erik De Clercq ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Entry ◽  
Mononuclear Cells ◽  
Human Immunodeficiency Virus Replication ◽  
Cxcr4 Antagonist ◽  
Peripheral Blood Mononuclear ◽  
Transfected Cells ◽  
Immunodeficiency Virus ◽  
Intracellular Ca ◽  
Hiv 1

ABSTRACT Here we report that the N-pyridinylmethyl cyclam analog AMD3451 has antiviral activity against a wide variety of R5, R5/X4, and X4 strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% inhibitory concentration [IC50] ranging from 1.2 to 26.5 μM) in various T-cell lines, CCR5- or CXCR4-transfected cells, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. AMD3451 also inhibited R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs (IC50, 1.8 to 7.3 μM). A PCR-based viral entry assay revealed that AMD3451 blocks R5 and X4 HIV-1 infection at the virus entry stage. AMD3451 dose-dependently inhibited the intracellular Ca2+ signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca2+ flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca2+ signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca2+ signaling by itself at concentrations up to 400 μM. In freshly isolated monocytes, AMD3451 inhibited the Ca2+ flux induced by CXCL12 and CCL4 but not that induced by CCL2, CCL3, CCL5, and CCL7. The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451. Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells. AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4. AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction.

scholarly journals Exogenous Interleukin-2 Administration Corrects the Cell Cycle Perturbation of Lymphocytes from Human Immunodeficiency Virus-Infected Individuals

2001 ◽  
Vol 75 (22) ◽  
pp. 10843-10855 ◽  
Author(s):  
Mirko Paiardini ◽  
Domenico Galati ◽  
Barbara Cervasi ◽  
Giuseppe Cannavo ◽  
Luca Galluzzi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Cycle Control ◽  
Interleukin 2 ◽  
Protein Ubiquitination ◽  
Immunodeficiency Virus ◽  
Cell Cycle Perturbation ◽  
Cycle Dependent

ABSTRACT Human immunodeficiency virus (HIV)-induced immunodeficiency is characterized by progressive loss of CD4+ T cells associated with functional abnormalities of the surviving lymphocytes. Increased susceptibility to apoptosis and loss of proper cell cycle control can be observed in lymphocytes from HIV-infected individuals and may contribute to the lymphocyte dysfunction of AIDS patients. To better understand the relation between T-cell activation, apoptosis, and cell cycle perturbation, we studied the effect of exogenous interleukin-2 (IL-2) administration on the intracellular turnover of phase-dependent proteins. Circulating T cells from HIV-infected patients display a marked discrepancy between a metabolic profile typical of G0 and a pattern of expression of phase-dependent proteins that indicates a more-advanced position within the cell cycle. This discrepancy is enhanced by in vitro activation with ConA and ultimately results in a marked increase of apoptotic events. Conversely, treatment of lymphocytes with IL-2 alone restores the phase-specific pattern of expression of cell cycle-dependent proteins and is associated with low levels of apoptosis. Interestingly, exogenous IL-2 administration normalizes the overall intracellular protein turnover, as measured by protein synthesis, half-life of newly synthesised proteins, and total protein ubiquitination, thus providing a possible explanation for the effect of IL-2 on the intracellular kinetics of cell cycle-dependent proteins. The beneficial effect of IL-2 administration is consistent with the possibility of defective IL-2 function in vivo, which is confirmed by the observation that lymphocytes from HIV-infected patients show abnormal endogenous IL-2 paracrine/autocrine function upon in vitro mitogen stimulation. Overall these results confirm that perturbation of cell cycle control contributes to HIV-related lymphocyte dysfunction and, by showing that IL-2 administration can revert this perturbation, suggest a new mechanism of action of IL-2 therapy in HIV-infected patients.

scholarly journals Protein Kinase A Phosphorylation Activates Vpr-Induced Cell Cycle Arrest during Human Immunodeficiency Virus Type 1 Infection

2010 ◽  
Vol 84 (13) ◽  
pp. 6410-6424 ◽  
Author(s):  
R. Anthony Barnitz ◽  
Fengyi Wan ◽  
Vinay Tripuraneni ◽  
Diane L. Bolton ◽  
Michael J. Lenardo
Keyword(s):  
Cell Cycle ◽  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
Cycle Arrest ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Kinase A

ABSTRACT Infection with human immunodeficiency virus type 1 (HIV-1) causes an inexorable depletion of CD4+ T cells. The loss of these cells is particularly pronounced in the mucosal immune system during acute infection, and the data suggest that direct viral cytopathicity is a major factor. Cell cycle arrest caused by the HIV-1 accessory protein Vpr is strongly correlated with virus-induced cell death, and phosphorylation of Vpr serine 79 (S79) is required to activate G2/M cell cycle blockade. However, the kinase responsible for phosphorylating Vpr remains unknown. Our bioinformatic analyses revealed that S79 is part of a putative phosphorylation site recognized by protein kinase A (PKA). We show here that PKA interacts with Vpr and directly phosphorylates S79. Inhibition of PKA activity during HIV-1 infection abrogates Vpr cell cycle arrest. These findings provide new insight into the signaling event that activates Vpr cell cycle arrest, ultimately leading to the death of infected T cells.

scholarly journals Efficient DNA Transfection Mediated by the C-Terminal Domain of Human Immunodeficiency Virus Type 1 Viral Protein R

2000 ◽  
Vol 74 (12) ◽  
pp. 5424-5431 ◽  
Author(s):  
Antoine Kichler ◽  
Jean-Christophe Pages ◽  
Christian Leborgne ◽  
Sabine Druillennec ◽  
Christine Lenoir ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Life Cycle ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Protein ◽  
Dna Transfection ◽  
Gag Protein ◽  
Viral Protein R ◽  
Immunodeficiency Virus

ABSTRACT Viral protein R (Vpr) of human immunodeficiency virus type 1 is produced late in the virus life cycle and is assembled into the virion through binding to the Gag protein. It is known to play a significant role early in the viral life cycle by facilitating the nuclear import of the preintegration complex in nondividing cells. Vpr is also able to interact with nucleic acids, and we show here that it induces condensation of plasmid DNA. We have explored the possibility of using these properties in DNA transfection experiments. We report that the C-terminal half of the protein (Vpr52–96) mediates DNA transfection in a variety of human and nonhuman cell lines with efficiencies comparable to those of the best-known transfection agents. Compared with polylysine, a standard polycationic transfection reagent, Vpr52–96 was 10- to 1,000-fold more active. Vpr52–96-DNA complexes were able to reach the cell nucleus through a pH-independent mechanism. These observations possibly identify an alternate pathway for DNA transfection.

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