HIV-1 at the immunological and T-lymphocytic virological synapse

2008 ◽  
Vol 389 (10) ◽  
Author(s):  
Claudia Haller ◽  
Oliver T. Fackler
Keyword(s):  
T Lymphocyte ◽  
Immunological Synapse ◽  
Virological Synapse ◽  
Viral Spread ◽  
Immunodeficiency Virus ◽  
Cellular Signal ◽  
Virological Synapses ◽  
Opposing Effects ◽  
Viral Transfer ◽  
Hiv 1

AbstractCell-cell transmission of human immunodeficiency virus type 1 (HIV-1) is considered the most effective mode of viral spread in T-lymphocyte cultures. Evidence has accumulated that HIV-1 assembles polarized synaptic-like structures, referred to as virological synapses, as specialized sites of viral transfer. Interestingly, it was recently also discovered that HIV-1 impairs the formation of the structurally similar immunological synapse, thereby modulating exogenous T-lymphocyte stimulation to yield an optimal activation state for productive HIV-1 infection. The careful dissection of these opposing effects will contribute to our understanding of retroviral spread and cellular signal transduction machineries.

scholarly journals Virological Synapse-Mediated Spread of Human Immunodeficiency Virus Type 1 between T Cells Is Sensitive to Entry Inhibition

2010 ◽  
Vol 84 (7) ◽  
pp. 3516-3527 ◽  
Author(s):  
Nicola Martin ◽  
Sonja Welsch ◽  
Clare Jolly ◽  
John A. G. Briggs ◽  
David Vaux ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Virological Synapse ◽  
Viral Spread ◽  
Immunodeficiency Virus ◽  
Virological Synapses ◽  
Hiv 1 ◽  
Entry Inhibition ◽  
Cell Cell

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) can disseminate between CD4+ T cells via diffusion-limited cell-free viral spread or by directed cell-cell transfer using virally induced structures termed virological synapses. Although T-cell virological synapses have been well characterized, it is unclear whether this mode of viral spread is susceptible to inhibition by neutralizing antibodies and entry inhibitors. We show here that both cell-cell and cell-free viral spread are equivalently sensitive to entry inhibition. Fluorescence imaging analysis measuring virological synapse lifetimes and inhibitor time-of-addition studies implied that inhibitors can access preformed virological synapses and interfere with HIV-1 cell-cell infection. This concept was supported by electron tomography that revealed the T-cell virological synapse to be a relatively permeable structure. Virological synapse-mediated HIV-1 spread is thus efficient but is not an immune or entry inhibitor evasion mechanism, a result that is encouraging for vaccine and drug design.

scholarly journals Predominant Mode of Human Immunodeficiency Virus Transfer between T Cells Is Mediated by Sustained Env-Dependent Neutralization-Resistant Virological Synapses

2007 ◽  
Vol 81 (22) ◽  
pp. 12582-12595 ◽  
Author(s):  
Ping Chen ◽  
Wolfgang Hübner ◽  
Matthew A. Spinelli ◽  
Benjamin K. Chen
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Productive Infection ◽  
Target Cells ◽  
Free Virus ◽  
Virus Transfer ◽  
Immunodeficiency Virus ◽  
Virological Synapses ◽  
Viral Transfer ◽  
Hiv 1

ABSTRACT Cell-free human immunodeficiency virus type 1 (HIV-1) can initiate infections, but contact between infected and uninfected T cells can enhance viral spread through intercellular structures called virological synapses (VS). The relative contribution of VS to cell-free viral transfer has not been carefully measured. Using an ultrasensitive, fluorescent virus transfer assay, we estimate that when VS between HIV-expressing Jurkat T cells and primary CD4+ T cells are formed, cell-associated transfer of virus is 18,000-fold more efficient than uptake of cell-free virus. Furthermore, in contrast to cell-free virus uptake, the VS deposits virus rapidly into focal, trypsin-resistant compartments in target T cells. This massive virus internalization requires Env-CD4 receptor interactions but is resistant to inhibition by patient-derived neutralizing antisera that inhibit homologous cell-free virus. Deleting the Env cytoplasmic tail does not abrogate VS-mediated transfer, but it renders the VS sensitive to neutralizing antibodies, suggesting that the tail limits exposure of VS-neutralizing epitopes on the surface of infected cells. Dynamic live imaging of the VS reveals that HIV-expressing cells are polarized and make sustained, Env-dependent contacts with target cells through uropod-like structures. The polarized T-cell morphology, Env-CD4 coordinated adhesion, and viral transfer from HIV-infected to uninfected cells suggest that VS allows HIV-1 to evade antibody neutralization and to disseminate efficiently. Future studies will discern to what extent this massive viral transfer contributes to productive infection or viral dissemination through the migration of virus-carrying T cells.

scholarly journals A Replication-Competent HIV Clone Carrying GFP-Env Reveals Rapid Env Recycling at the HIV-1 T Cell Virological Synapse

Viruses ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 38
Author(s):  
Lili Wang ◽  
Alice Sandmeyer ◽  
Wolfgang Hübner ◽  
Hongru Li ◽  
Thomas Huser ◽  
...  
Keyword(s):  
Virological Synapse ◽  
Target Cells ◽  
Structural Protein ◽  
Combined Use ◽  
Infected Cells ◽  
Virological Synapses ◽  
Dynamic Exchange ◽  
Endocytic Compartments ◽  
Viral Transfer ◽  
Hiv 1

HIV-1 infection is enhanced by cell–cell adhesions between infected and uninfected T cells called virological synapses (VS). VS are initiated by the interactions of cell-surface HIV-1 envelope glycoprotein (Env) and CD4 on target cells and act as sites of viral assembly and viral transfer between cells. To study the process that recruits and retains HIV-1 Env at the VS, a replication-competent HIV-1 clone carrying an Env-sfGFP fusion protein was designed to enable live tracking of Env within infected cells. Combined use of surface pulse-labeling of Env and fluorescence recovery after photobleaching (FRAP) studies, enabled the visualization of the targeted accumulation and sustained recycling of Env between endocytic compartments (EC) and the VS. We observed dynamic exchange of Env at the VS, while the viral structural protein, Gag, was largely immobile at the VS. The disparate exchange rates of Gag and Env at the synapse support that the trafficking and/or retention of a majority of Env towards the VS is not maintained by entrapment by a Gag lattice or immobilization by binding to CD4 on the target cell. A FRAP study of an Env endocytosis mutant showed that recycling is not required for accumulation at the VS, but is required for the rapid exchange of Env at the VS. We conclude that the mechanism of Env accumulation at the VS and incorporation into nascent particles involves continuous internalization and targeted secretion rather than irreversible interactions with the budding virus, but that this recycling is largely dispensable for VS formation and viral transfer across the VS.

scholarly journals Recruitment of Env to the HIV-1 T cell virological synapse by targeted and sustained Env recycling

2020 ◽  
Author(s):  
Lili Wang ◽  
Alice Sandmeyer ◽  
Wolfgang Hübner ◽  
Hongru Li ◽  
Thomas Huser ◽  
...  
Keyword(s):  
Fluorescence Recovery After Photobleaching ◽  
Virological Synapse ◽  
Target Cells ◽  
Structural Protein ◽  
Rapid Exchange ◽  
Infected Cells ◽  
Virological Synapses ◽  
Dynamic Exchange ◽  
Viral Transfer ◽  
Hiv 1

ABSTRACTHIV-1 infection is enhanced by cell-cell adhesions between infected and uninfected T cells called virological synapses (VS). VS are initiated by the interactions of cell-surface HIV-1 envelope glycoprotein (Env) and CD4 on target cells and act as sites of viral assembly and viral transfer between cells. To study the process that recruits and retains HIV-1 Env at the VS, a replication-competent HIV-1 clone carrying an Env-sfGFP fusion protein was designed to enable live tracking of Env within infected cells. Using surface pulse-labeling of Env and fluorescence recovery after photobleaching (FRAP) studies, we observed targeted accumulation and sustained recycling of Env between the endocytic recycling compartment (ERC) and the VS. We observed dynamic exchange of Env at the VS while the viral structural protein, Gag, was largely immobile at the VS. The disparate exchange rates of Gag and Env at the synapse indicate that retention of Env is not likely to be maintained by entrapment into an immobile Gag lattice or through immobilizing interactions with CD4 on the target cell. A FRAP study of an Env endocytosis mutant showed that recycling is required for the rapid exchange of Env at the VS. We conclude that the mechanism of Env accumulation at the VS and incorporation into nascent particles involves continuous internalization and targeted secretion rather than irreversible interactions with the budding virus.

scholarly journals Human Immunodeficiency Virus Type 1 Envelope gp120 Induces a Stop Signal and Virological Synapse Formation in Noninfected CD4+ T Cells

2008 ◽  
Vol 82 (19) ◽  
pp. 9445-9457 ◽  
Author(s):  
Gaia Vasiliver-Shamis ◽  
Michael Tuen ◽  
Teresa W. Wu ◽  
Toby Starr ◽  
Thomas O. Cameron ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Immunological Synapse ◽  
Stop Signal ◽  
Virological Synapse ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Envelope Gp120

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected T cells form a virological synapse with noninfected CD4+ T cells in order to efficiently transfer HIV-1 virions from cell to cell. The virological synapse is a specialized cellular junction that is similar in some respects to the immunological synapse involved in T-cell activation and effector functions mediated by the T-cell antigen receptor. The immunological synapse stops T-cell migration to allow a sustained interaction between T-cells and antigen-presenting cells. Here, we have asked whether HIV-1 envelope gp120 presented on a surface to mimic an HIV-1-infected cell also delivers a stop signal and if this is sufficient to induce a virological synapse. We demonstrate that HIV-1 gp120-presenting surfaces arrested the migration of primary activated CD4 T cells that occurs spontaneously in the presence of ICAM-1 and induced the formation of a virological synapse, which was characterized by segregated supramolecular structures with a central cluster of envelope surrounded by a ring of ICAM-1. The virological synapse was formed transiently, with the initiation of migration within 30 min. Thus, HIV-1 gp120-presenting surfaces induce a transient stop signal and supramolecular segregation in noninfected CD4+ T cells.

scholarly journals HIV-1 Virological Synapse is not Simply a Copycat of the Immunological Synapse

Viruses ◽  
2010 ◽  
Vol 2 (5) ◽  
pp. 1239-1260 ◽  
Author(s):  
Gaia Vasiliver-Shamis ◽  
Michael Dustin ◽  
Catarina Hioe
Keyword(s):  
Immunological Synapse ◽  
Virological Synapse ◽  
Hiv 1

scholarly journals Discordant Outcomes following Failure of Antiretroviral Therapy Are Associated with Substantial Differences in Human Immunodeficiency Virus-Specific Cellular Immunity

2003 ◽  
Vol 77 (10) ◽  
pp. 6041-6049 ◽  
Author(s):  
David A. Price ◽  
George Scullard ◽  
Annette Oxenius ◽  
Ruth Braganza ◽  
Simon A. Beddows ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
T Lymphocyte ◽  
Virologic Failure ◽  
Multiple Drug Resistance ◽  
Testable Hypothesis ◽  
Plasma Virus ◽  
Immunodeficiency Virus ◽  
Lymphocyte Responses ◽  
Hiv 1

ABSTRACT Many individuals chronically infected with human immunodeficiency virus type 1 (HIV-1) experience a recrudescence of plasma virus during continuous combination antiretroviral therapy (ART) due either to the emergence of drug-resistant viruses or to poor compliance. In most cases, virologic failure on ART is associated with a coincident decline in CD4+ T lymphocyte levels. However, a proportion of discordant individuals retain a stable or even increasing CD4+ T lymphocyte count despite virological failure. In order to address the nature of these different outcomes, we evaluated virologic and immunologic variables in a prospective, single-blinded, nonrandomized cohort of 53 subjects with chronic HIV-1 infection who had been treated with continuous ART and monitored intensively over a period of 19 months. In all individuals with detectable viremia on ART, multiple drug resistance mutations with similar impacts on viral growth kinetics were detected in the pol gene of circulating plasma virus. Further, C2V3 env gene analysis demonstrated sequences indicative of CCR5 coreceptor usage in the majority of those with detectable plasma viremia. In contrast to this homogeneous virologic pattern, comprehensive screening with a range of antigens derived from HIV-1 revealed substantial immunologic differences. Discordant subjects with stable CD4+ T lymphocyte counts in the presence of recrudescent virus demonstrated potent virus-specific CD4+ and CD8+ T lymphocyte responses. In contrast, subjects with virologic failure associated with declining CD4+ T lymphocyte counts had substantially weaker HIV-specific CD4+ T lymphocyte responses and exhibited a trend towards weaker HIV-specific CD8+ T lymphocyte responses. Importantly the CD4+ response was sustained over periods as long as 11 months, confirming the stability of the phenomenon. These correlative data lead to the testable hypothesis that the consequences of viral recrudescence during continuous ART are modulated by the HIV-specific cellular immune response.

scholarly journals Relative contribution of free-virus and synaptic transmission to the spread of HIV-1 through target cell populations

2013 ◽  
Vol 9 (1) ◽  
pp. 20121049 ◽  
Author(s):  
Natalia L. Komarova ◽  
Daniela Anghelina ◽  
Igor Voznesensky ◽  
Benjamin Trinité ◽  
David N. Levy ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Target Cells ◽  
Free Virus ◽  
Virus Growth ◽  
Relative Contribution ◽  
Immunodeficiency Virus ◽  
Virological Synapses ◽  
Transmission Pathways ◽  
Hiv 1

Human immunodeficiency virus can spread through target cells by transmission of cell-free virus or directly from cell-to-cell via formation of virological synapses. Although cell-to-cell transmission has been described as much more efficient than cell-free infection, the relative contribution of the two transmission pathways to virus growth during multiple rounds of replication remains poorly defined. Here, we fit a mathematical model to previously published and newly generated in vitro data, and determine that free-virus and synaptic transmission contribute approximately equally to the growth of the virus population.

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