Actin Dynamics Regulates Dendritic Cell-Mediated Transfer of HIV-1 to T Cells

Ménager, Mickaël M.; Littman, Dan R.

doi:10.1016/j.cell.2015.12.036

Cited by 81 publications

(96 citation statements)

References 54 publications

(80 reference statements)

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“…This analysis revealed significant enrichment of, among others, genes involved in focal adhesion (Figure 1E). Among these were CFL1, a protein that depolymerizes F-actin and that, upon knockdown, was shown to enhance transinfection of HIV-1 between dendritic cells (DCs) and T lymphocytes (Ménager and Littman, 2016); CD99, which is involved in T cell adhesion and leukocyte migration (Bernard et al, 2000; Hahn et al, 1997; Sohn et al, 2001); and ATP1B1, which is a subunit of the Na + /K + transporter. These results suggest that Vpu-mediated immune evasion strategies may affect a broader range of host cell functions than previously appreciated, including host metabolic processes and plasma membrane activities.…”

Section: Resultsmentioning

confidence: 99%

Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

et al. 2018

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SUMMARY Accessory proteins of lentiviruses, such as HIV-1, target cellular restriction factors to enhance viral replication. Systematic analyses of proteins that are targeted for degradation by HIV-1 accessory proteins may provide a better understanding of viral immune evasion strategies. Here, we describe a high-throughput platform developed to study cellular protein stability in a highly parallelized matrix format. We used this approach to identify cellular targets of the HIV-1 accessory protein Vpu through arrayed coexpression with 433 interferon-stimulated genes, followed by differential fluorescent labeling and automated image analysis. Among the previously unreported Vpu targets identified by this approach, we find that the E2 ligase mediating ISG15 conjugation, UBE2L6, and the transmembrane protein PLP2 are targeted by Vpu during HIV-1 infection to facilitate late-stage replication. This study provides a framework for the systematic and high-throughput evaluation of protein stability and establishes a more comprehensive portrait of cellular Vpu targets.

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Section: Resultsmentioning

confidence: 99%

Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

et al. 2018

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“…We suspect that this controversy in the field debating whether or not HIV-1 gets inside the cell through endocytosis (Marin and Melikyan, 2015) has deviated the attention from the actual role of DNM2 during HIV-1 fusion. Nevertheless, there is growing interest in the field to understand the role of actin dynamics in HIV infection: a recent report (Ménager and Littman, 2016) points at the importance of DNM2 in dendritic cells mediated trans-enhancement of CD4 T cell infection by HIV in vitro. In this scenario, insights about the true role of DNM2 during single virus fusion are needed to fully understand the mechanisms taking place (Padilla-Parra and Dustin, 2016).…”

Section: Discussionmentioning

confidence: 99%

Dynamin-2 Stabilizes the HIV-1 Fusion Pore with a Low Oligomeric State

et al. 2017

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SummaryOne of the key research areas surrounding HIV-1 concerns the regulation of the fusion event that occurs between the virus particle and the host cell during entry. Even if it is universally accepted that the large GTPase dynamin-2 is important during HIV-1 entry, its exact role during the first steps of HIV-1 infection is not well characterized. Here, we have utilized a multidisciplinary approach to study the DNM2 role during fusion of HIV-1 in primary resting CD4 T and TZM-bl cells. We have combined advanced light microscopy and functional cell-based assays to experimentally assess the role of dynamin-2 during these processes. Overall, our data suggest that dynamin-2, as a tetramer, might help to establish hemi-fusion and stabilizes the pore during HIV-1 fusion.

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“…However, studies have also shown that DC-SIGN mediated internalized HIV-1 particles undergo degradation and subsequent presentation of HIV-1 antigen to T-cells535455. Recent research indicates that surface-bound HIV-1 on DCs is more effectively transmitted to T-cells, rather than the internalized HIV-1 particle3137565758.…”

Section: Discussionmentioning

confidence: 99%

Cocaine Enhances DC to T-cell HIV-1 Transmission by Activating DC-SIGN/LARG/LSP1 Complex and Facilitating Infectious Synapse Formation

Kulkarni

Jiang

Groopman

2017

Sci Rep

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DC-SIGN is a dendritic cell surface structure which participates in binding and transmission of HIV-1. Here, for the first time we demonstrate that cocaine induces over expression of DC-SIGN and significantly enhances virus transfer from DCs to T-cells by increasing the binding and internalization of HIV-1 in DCs. We found that cocaine activates a DC-SIGN mediated ‘signalosome’ complex by enhancing its association with LARG and LSP1. Further, LARG was observed to participate in DC-SIGN mediated internalization of HIV-1 in DCs. Intracellular trafficking studies of HIV-1 in cocaine treated DCs revealed increased co-localization of HIV-1 with endosomal or multi vesicular body (MVB) markers such as CD81 and VPS4 and decreased co-localization with the phagolysomal marker LAMP1; this signified altered intracellular trafficking and decreased degradation of HIV-1 in cocaine treated DCs. Furthermore, we found that cocaine induced activation of LARG which in turn activated Rho A and the focal adhesion molecules FAK, Pyk2 and paxillin. This signaling cascade enhanced the formation of an infectious synapse between DCs and T-cells. Our study provides insight into the molecular mechanisms of cocaine’s contribution to key components in HIV pathogenesis and highlights novel targets for interrupting the virus life cycle in substance using hosts.

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Actin Dynamics Regulates Dendritic Cell-Mediated Transfer of HIV-1 to T Cells

Cited by 81 publications

References 54 publications

Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

Dynamin-2 Stabilizes the HIV-1 Fusion Pore with a Low Oligomeric State

Cocaine Enhances DC to T-cell HIV-1 Transmission by Activating DC-SIGN/LARG/LSP1 Complex and Facilitating Infectious Synapse Formation

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