Human Immunodeficiency Virus (HIV)-Resistant CD4+ UT-7 Megakaryocytic Human Cell Line Becomes Highly HIV-1 and HIV-2 Susceptible Upon CXCR4 Transfection: Induction of Cell Differentiation by HIV-1 Infection

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2670-2678 ◽  
Author(s):  
Marta Baiocchi ◽  
Eleonora Olivetta ◽  
Cristiana Chelucci ◽  
Anna Claudia Santarcangelo ◽  
Roberta Bona ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Cell Line ◽  
Viral Entry ◽  
Human Cell Line ◽  
Immunodeficiency Virus ◽  
Hiv Entry ◽  
Stromal Cell Derived Factor ◽  
Hiv 1

Abstract Recent findings have shown that the expression of the seven trans-membrane G-protein–coupled CXCR4 (the receptor for the stromal cell-derived factor [SDF]-1 chemokine) is necessary for the entry of T-lymphotropic human immunodeficiency virus (HIV) strains, acting as a coreceptor of the CD4 molecule. In the human system, the role of CXCR4 in HIV infection has been determined through env-mediated cell fusion assays and confirmed by blocking viral entry in CD4+/CXCR4+ cells by SDF-1 pretreatment. We observed that the human megakaryoblastic CD4+ UT-7 cell line fails to express CXCR4 RNA and is fully resistant to HIV entry. Transfection of an expression vector containing the CXCR4 c-DNA rendered UT-7 cells readily infectable by different T-lymphotropic syncytium-inducing HIV-1 and HIV-2 isolates. Interestingly, HIV-1 infection of CXCR4 expressing UT-7 cells (named UT-7/fus) induces the formation of polynucleated cells through a process highly reminiscent of megakaryocytic differentiation and maturation. On the contrary, no morphologic changes were observed in HIV-2–infected UT-7/fus cells. These findings further strengthen the role of CXCR4 as a molecule necessary for the replication of T-lymphotropic HIV-1 and HIV-2 isolates and provide a useful model to study the functional role of CD4 coreceptors in HIV infection.

scholarly journals Replacement of the V3 Region of gp120 with SDF-1 Preserves the Infectivity of T-Cell Line-Tropic Human Immunodeficiency Virus Type 1

2001 ◽  
Vol 75 (9) ◽  
pp. 4258-4267 ◽  
Author(s):  
Akihito Yonezawa ◽  
Toshiyuki Hori ◽  
Akifumi Takaori-Kondo ◽  
Rinpei Morita ◽  
Takashi Uchiyama
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Cell Line ◽  
Human Immunodeficiency Virus Type ◽  
Viral Entry ◽  
Expression Vector ◽  
Immunodeficiency Virus ◽  
V3 Region ◽  
Hiv 1

ABSTRACT Interaction between the human immunodeficiency virus type 1 (HIV-1) envelope and the relevant chemokine receptors is crucial for subsequent membrane fusion and viral entry. Although the V3 region of gp120 is known to determine the cell tropism as well as the coreceptor usage, the significance of the binding of the V3 region to the chemokine receptor has not been fully understood. To address this issue, we adopted the pseudotyped virus infection assay in which the V3 region of the T-cell line-tropic (T-tropic) NL4-3 envelope was replaced with a portion of stromal cell-derived factor 1 (SDF-1), the ligand of CXCR4. The V3 region of the NL4-3 envelope expression vector was replaced with three different stretches of SDF-1 cDNA. Expression of each chimeric envelope protein was confirmed by immunoprecipitation and Western blotting. Luciferase reporter viruses were prepared by cotransfection of the pNL4-3.Luc.E−R− vector and each chimeric envelope expression vector, and the infection assay was then carried out. We showed that pseudotyped viruses with one of the chimeric envelopes, NL4-3/SDF1-51, could infect U87.CD4.CXCR4 but not U87.CD4 or U87.CXCR4 cells and that this infection was inhibited by the ligand of CXCR4, SDF-1β, by anti-human SDF-1 antibody, or by an anti-CD4 antibody, Leu3a, in a dose-dependent manner. Furthermore, chimeric NL4-3/SDF1-51 gp120 significantly inhibited binding of labeled SDF-1 to CXCR4. It was suggested that replacement of the V3 region of the NL4-3 envelope with SDF-1 preserved the CD4-dependent infectivity of T-tropic HIV-1. These results indicate that binding between the V3 region and the relevant coreceptor is important for viral entry, whether its amino acid sequence is indigenous to the virus or not.

Human Immunodeficiency Virus Replication Induces Monocyte Chemotactic Protein-1 in Human Macrophages and U937 Promonocytic Cells

Blood ◽  
1999 ◽  
Vol 93 (6) ◽  
pp. 1851-1857 ◽  
Author(s):  
Manuela Mengozzi ◽  
Camilla De Filippi ◽  
Pietro Transidico ◽  
Priscilla Biswas ◽  
Manuela Cota ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Cell Line ◽  
U937 Cells ◽  
Hiv Replication ◽  
Monocyte Chemotactic Protein ◽  
Chemotactic Protein ◽  
Immunodeficiency Virus ◽  
The Brain ◽  
Hiv 1

We have recently described a significant correlation between human immunodeficiency virus-1 (HIV-1) RNA replication and monocyte chemotactic protein-1 (MCP-1) levels in the cerebrospinal fluid (CSF) of individuals with the acquired immunodeficiency syndrome (AIDS) with HIV encephalitis (E). Because local macrophages (microglia) are the cells predominantly infected in the brain, we investigated whether in vitro HIV infection affects MCP-1 production in mononuclear phagocytes (MP). MCP-1 secretion and expression were consinstently upregulated over constitutive levels in human monocyte-derived macrophages (MDM) infected with the M-tropic R5 BaL strain of HIV-1. HIV replication was required for this effect, as demonstrated by the absence of chemokine upregulation after infection in the presence of 3’-azido-3’-deoxythimidine (AZT) or cell-exposure to heat-inactivated (▵°) virus. MCP-1 induction was not restricted to HIV-1 BaL, but was also observed during productive infection of MDM with two primary isolates differing for entry coreceptor usage and of U937 cells with the X4 HIV-1 MN strain. Based on the observation that exogenous HIV-1 Tat induced MCP-1 expression in astrocytes, we also investigated its role in MDM and U937 cells. Exogenous Tat induced MCP-1 production from MDM in a concentration-dependent manner, however, it was not effective on uninfected U937 cells or on the chronically infected U937-derived cell line U1. Transfection of Tat-expressing plasmids moderately activated HIV expression in U1 cells, but failed to induce MCP-1 expression in this cell line or in uninfected U937 cells. HIV replication-dependent expression of MCP-1 in MP may be of particular relevance for the pathogenesis of HIV infection in nonlymphoid organs such as the brain.

scholarly journals Lineage-Specific Differences between the gp120 Inner Domain Layer 3 of Human Immunodeficiency Virus and That of Simian Immunodeficiency Virus

2016 ◽  
Vol 90 (22) ◽  
pp. 10065-10073 ◽  
Author(s):  
Shilei Ding ◽  
Halima Medjahed ◽  
Jérémie Prévost ◽  
Mathieu Coutu ◽  
Shi-Hua Xiang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Simian Immunodeficiency Virus ◽  
Conformational Changes ◽  
Viral Entry ◽  
Chemokine Receptors ◽  
Immunodeficiency Virus ◽  
Layer 2 ◽  
Hiv 1

ABSTRACT Binding of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) gp120 exterior envelope glycoprotein to CD4 triggers conformational changes in gp120 that promote its interaction with one of the chemokine receptors, usually CCR5, ultimately leading to gp41-mediated virus-cell membrane fusion and entry. We previously described that topological layers (layer 1, layer 2, and layer 3) in the gp120 inner domain contribute to gp120-trimer association in the unliganded state but also help secure CD4 binding. Relative to layer 1 of HIV-1 gp120, the SIVmac239 gp120 layer 1 plays a more prominent role in maintaining gp120-trimer association but is minimally involved in promoting CD4 binding, which could be explained by the existence of a well-conserved tryptophan at position 375 (Trp 375) in HIV-2/SIVsmm. In this study, we investigated the role of SIV layer 3 in viral entry, cell-to-cell fusion, and CD4 binding. We observed that a network of interactions involving some residues of the β8-α5 region in SIVmac239 layer 3 may contribute to CD4 binding by helping shape the nearby Phe 43 cavity, which directly contacts CD4. In summary, our results suggest that layer 3 in SIV has a greater impact on CD4 binding than in HIV-1. This work defines lineage-specific differences in layer 3 from HIV-1 and that from SIV. IMPORTANCE CD4-induced conformational changes in the gp120 inner domain involve rearrangements between three topological layers. While the role of layers 1 to 3 for HIV-1 and layers 1 and 2 for SIV on gp120 transition to the CD4-bound conformation has been reported, the role of SIV layer 3 remains unknown. Here we report that SIV layer 3 has a greater impact on CD4 binding than does layer 3 in HIV-1 gp120. This work defines lineage-specific differences in layer 3 from HIV-1 and SIV.

scholarly journals From Capsids to Complexes: Expanding the Role of TRIM5α in the Restriction of Divergent RNA Viruses and Elements

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 446
Author(s):  
Kevin M. Rose ◽  
Stephanie J. Spada ◽  
Rebecca Broeckel ◽  
Kristin L. McNally ◽  
Vanessa M. Hirsch ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Molecular Basis ◽  
Human Population ◽  
Rna Viruses ◽  
Arms Race ◽  
Innate Immune ◽  
Immunodeficiency Virus ◽  
Underlying Mechanisms ◽  
Hiv 1

An evolutionary arms race has been ongoing between retroviruses and their primate hosts for millions of years. Within the last century, a zoonotic transmission introduced the Human Immunodeficiency Virus (HIV-1), a retrovirus, to the human population that has claimed the lives of millions of individuals and is still infecting over a million people every year. To counteract retroviruses such as this, primates including humans have evolved an innate immune sensor for the retroviral capsid lattice known as TRIM5α. Although the molecular basis for its ability to restrict retroviruses is debated, it is currently accepted that TRIM5α forms higher-order assemblies around the incoming retroviral capsid that are not only disruptive for the virus lifecycle, but also trigger the activation of an antiviral state. More recently, it was discovered that TRIM5α restriction is broader than previously thought because it restricts not only the human retroelement LINE-1, but also the tick-borne flaviviruses, an emergent group of RNA viruses that have vastly different strategies for replication compared to retroviruses. This review focuses on the underlying mechanisms of TRIM5α-mediated restriction of retroelements and flaviviruses and how they differ from the more widely known ability of TRIM5α to restrict retroviruses.

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 Interleukin 7 Increases Human Immunodeficiency Virus Type 1 LAI-Mediated Fas-Induced T-Cell Death

2005 ◽  
Vol 79 (5) ◽  
pp. 3195-3199 ◽  
Author(s):  
Jean-Daniel Lelièvre ◽  
Frédéric Petit ◽  
Damien Arnoult ◽  
Jean-Claude Ameisen ◽  
Jérôme Estaquier
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Infection ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Fas-mediated T-cell death is known to occur during human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 LAI (HIV-1LAI) primes CD8+ T cells from healthy donors for apoptosis, which occurs after Fas ligation. This effect is counteracted by a broad caspase inhibitor (zVAD-fmk). Fas-mediated cell death does not depend on CD8+ T-cell infection, because it occurred in the presence of reverse transcriptase inhibitors. However, purified CD8+ T cells are sensitive to Fas only in the presence of soluble CD4. Finally, we found that interleukin 7 (IL-7) increases Fas-mediated CD4+ and CD8+ T-cell death induced by HIV-1LAI. Since high levels of IL-7 are a marker of poor prognosis during HIV infection, our data suggest that enhancement of Fas-mediated T-cell death by HIV-1LAI and IL-7 is one of the mechanisms involved in progression to AIDS.

scholarly journals Human Immunodeficiency Virus Inhibits Multilineage Hematopoiesis In Vivo

1998 ◽  
Vol 72 (6) ◽  
pp. 5121-5127 ◽  
Author(s):  
Prasad S. Koka ◽  
John K. Fraser ◽  
Yvonne Bryson ◽  
Gregory C. Bristol ◽  
Grace M. Aldrovandi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Ex Vivo ◽  
Erythroid Differentiation ◽  
Inhibitory Effect ◽  
Immunodeficiency Virus ◽  
The Many ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected individuals often exhibit multiple hematopoietic abnormalities reaching far beyond loss of CD4+ lymphocytes. We used the SCID-hu (Thy/Liv) mouse (severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues), which provides an in vivo system whereby human pluripotent hematopoietic progenitor cells can be maintained and undergo T-lymphoid differentiation and wherein HIV-1 infection causes severe depletion of CD4-bearing human thymocytes. Herein we show that HIV-1 infection rapidly and severely decreases the ex vivo recovery of human progenitor cells capable of differentiation into both erythroid and myeloid lineages. However, the total CD34+ cell population is not depleted. Combination antiretroviral therapy administered well after loss of multilineage progenitor activity reverses this inhibitory effect, establishing a causal role of viral replication. Taken together, our results suggest that pluripotent stem cells are not killed by HIV-1; rather, a later stage important in both myeloid and erythroid differentiation is affected. In addition, a primary virus isolated from a patient exhibiting multiple hematopoietic abnormalities preferentially depleted myeloid and erythroid colony-forming activity rather than CD4-bearing thymocytes in this system. Thus, HIV-1 infection perturbs multiple hematopoietic lineages in vivo, which may explain the many hematopoietic defects found in infected patients.

scholarly journals Use of Coreceptors Other Than CCR5 by Non-Syncytium-Inducing Adult and Pediatric Isolates of Human Immunodeficiency Virus Type 1 Is Rare In Vitro

1998 ◽  
Vol 72 (11) ◽  
pp. 9337-9344 ◽  
Author(s):  
Yi-jun Zhang ◽  
Tatjana Dragic ◽  
Yunzhen Cao ◽  
Leondios Kostrikis ◽  
Douglas S. Kwon ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Entry ◽  
Infected Infant ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We have tested a panel of pediatric and adult human immunodeficiency virus type 1 (HIV-1) primary isolates for the ability to employ the following proteins as coreceptors during viral entry: CCR1, CCR2b, CCR3, CCR4, CCR5, CCR8, CXCR4, Bonzo, BOB, GPR1, V28, US28, and APJ. Most non-syncytium-inducing isolates could utilize only CCR5. All syncytium-inducing viruses used CXCR4, some also employed V28, and one (DH123) used CCR8 and APJ as well. A longitudinal series of HIV-1 subtype B isolates from an infected infant and its mother utilized Bonzo efficiently, as well as CCR5. The maternal isolates, which were syncytium inducing, also used CXCR4, CCR8, V28, and APJ.

scholarly journals Role of Vif in Stability of the Human Immunodeficiency Virus Type 1 Core

2000 ◽  
Vol 74 (23) ◽  
pp. 11055-11066 ◽  
Author(s):  
Åsa Öhagen ◽  
Dana Gabuzda
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dna Synthesis ◽  
Virus Entry ◽  
Wild Type ◽  
The Core ◽  
Immunodeficiency Virus ◽  
The Stability ◽  
Hiv 1

ABSTRACT The Vif protein of human immunodeficiency virus type 1 (HIV-1) is important for virion infectivity. Previous studies have shown thatvif-defective virions exhibit structural abnormalities in the virus core and are defective in the ability to complete proviral DNA synthesis in acutely infected cells. We developed novel assays to assess the relative stability of the core in HIV-1 virions. Using these assays, we examined the role of Vif in the stability of the HIV-1 core. The integrity of the core was examined following virion permeabilization or removal of the lipid envelope and treatment with various triggers, including S100 cytosol, deoxynucleoside triphosphates, detergents, NaCl, and buffers of different pH to mimic aspects of the uncoating and disassembly process which occurs after virus entry but preceding or during reverse transcription.vif mutant cores were more sensitive to disruption by all triggers tested than wild-type cores, as determined by endogenous reverse transcriptase (RT) assays, biochemical analyses, and electron microscopy. RT and the p7 nucleocapsid protein were released more readily from vif mutant virions than from wild-type virions, suggesting that the internal nucleocapsid is less stably packaged in the absence of Vif. Purified cores could be isolated from wild-type but not vif mutant virions by sedimentation through detergent-treated gradients. These results demonstrate that Vif increases the stability of virion cores. This may permit efficient viral DNA synthesis by preventing premature degradation or disassembly of viral nucleoprotein complexes during early events after virus entry.

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