Wang, J. H., Wells, C. & Wu, L. Macropinocytosis and cytoskeleton contribute to dendritic cell-mediated HIV-1 transmission to CD4+ T cells. Virology 381, 143-154

Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Virology (Impact Factor: 3.32). 10/2008; 381(1):143-54. DOI: 10.1016/j.virol.2008.08.028
Source: PubMed


Dendritic cells (DCs) are among the first immune cells to encounter HIV-1 at the initial infection. DCs efficiently transfer HIV-1 to CD4+ T cells via infectious or virological synapses formed between DCs and T cells. Retroviruses exploit the cytoskeletal network to facilitate viral infection and dissemination; however, the role of the cytoskeleton in DC-mediated HIV-1 transmission is unknown. Here, we report that intact cytoskeleton is essential for DC-mediated HIV-1 transmission to CD4+ T cells. We found that macropinocytosis of HIV-1 contributes to DC-mediated HIV-1 endocytosis and transmission. Blocking HIV-1 macropinocytosis and disrupting actin or microtubules in DCs with specific inhibitors significantly prevented DC-mediated HIV-1 trans-infection of CD4+ T cells. Altered HIV-1 trafficking and impaired formation of virological synapses primarily accounted for the inhibition of viral transmission by cytoskeletal inhibitors. Our results provide new insights into the mechanisms underlying DC-mediated HIV-1 transmission to CD4+ T cells via the cytoskeletal network.

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Available from: Clive Wells, Jul 10, 2014
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    • "This observation is consistent with the findings of other authors, who have demonstrated the relevance of ICAM-1 and LFA-1 [34,37], but not of ICAM-3 [37], in the DC-mediated transmission of HIV-1 across the infectious synapse. As with the virological synapse [11,56], and according to the results of other authors [67], we confirmed that the formation of the infectious synapse was an actin-dependent process. Remodeling of the actin cytoskeleton not only enables recruitment of receptors to the interface between mDC and CD4+ T cells to facilitate transmission of HIV-1 [12], but it also enables HIV-1 polarization and sac-like compartment formation in mDC upon viral capture [27,32]. "
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    ABSTRACT: Background Since cell-mediated infection of human immunodeficiency virus type 1 (HIV-1) is more efficient than cell-free infection, cell-to-cell propagation plays a crucial role in the pathogenesis of HIV-1 infection. Transmission of HIV-1 is enabled by two types of cellular contacts, namely, virological synapses between productively infected cells and uninfected target cells and infectious synapses between uninfected dendritic cells (DC) harboring HIV-1 and uninfected target cells. While virological synapses are driven by expression of the viral envelope glycoprotein on the cell surface, little is known about the role of envelope glycoprotein during contact between DC and T cells. We explored the contribution of HIV-1 envelope glycoprotein, adhesion molecules, and antigen recognition in the formation of conjugates comprising mature DC (mDC) and CD4+ T cells in order to further evaluate their role in mDC-mediated HIV-1 transmission at the immunological synapse. Results Unlike virological synapse, HIV-1 did not modulate the formation of cell conjugates comprising mDC harboring HIV-1 and non-activated primary CD4+ T cells. Disruption of interactions between ICAM-1 and LFA-1, however, resulted in a 60% decrease in mDC-CD4+ T-cell conjugate formation and, consequently, in a significant reduction of mDC-mediated HIV-1 transmission to non-activated primary CD4+ T cells (p < 0.05). Antigen recognition or sustained MHC-TcR interaction did not enhance conjugate formation, but significantly boosted productive mDC-mediated transmission of HIV-1 (p < 0.05) by increasing T-cell activation and proliferation. Conclusions Formation of the infectious synapse is independent of the presence of the HIV-1 envelope glycoprotein, although it does require an interaction between ICAM-1 and LFA-1. This interaction is the main driving force behind the formation of mDC-CD4+ T-cell conjugates and enables transmission of HIV-1 to CD4+ T cells. Moreover, antigen recognition boosts HIV-1 replication without affecting the frequency of cellular conjugates. Our results suggest a determinant role for immune activation driven by mDC-CD4+ T-cell contacts in viral dissemination and that this activation likely contributes to the pathogenesis of HIV-1 infection.
    Full-text · Article · Apr 2013 · Retrovirology
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    • "Disruption of both macropinocytosis and cytoskeleton, using specific inhibitors, alters HIV-1 trafficking and inhibits DC-mediated HIV-1 transmission to CD4 + T cells (Wang et al. 2008). DC-mediated HIV-1 transmission to CD4 + T cells is inhibited because of impaired formation of the VS (Wang et al. 2008), indicating that HIV-1 exploits macropinocytosis and the cytoskeletal network to promote formation of the VS, allowing efficient HIV-1 transmission and dissemination. "
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    ABSTRACT: Dendritic cells (DCs) play a key role in the initial infection and cell-to-cell transmission events that occur upon HIV-1 infection. DCs interact closely with CD4(+) T cells, the main target of HIV-1 replication. HIV-1 challenged DCs and target CD4(+) T cells form a virological synapse that allows highly efficient transmission of HIV-1 to the target CD4(+) T cells, in the absence of productive HIV-1 replication in the DCs. Immature and subsets of mature DCs show distinct patterns of HIV-1 replication and cell-to-cell transmission, depending upon the maturation stimulus that is used. The cellular and viral mechanisms that promote formation of the virological synapse have been the subject of intense study and the most recent progress is discussed here. Characterizing the cellular and viral factors that affect DC-mediated cell-to-cell transmission of HIV-1 to CD4(+) T cells is vitally important to understanding, and potentially blocking, the initial dissemination of HIV-1 in vivo.
    Full-text · Article · Jan 2013 · Advances in Experimental Medicine and Biology
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    • "This study also suggests that macropinocytosis is induced by the interaction of HIV-1 with CXCR4 on host cell membranes, which leads to the internalization of the receptor during viral infection of the host cells. Although the involvement of macropinocytosis with HIV-1 internalization has been observed in specific cells such as dendritic cells (Wang et al., 2008), macropinocytosis operates only for housekeeping in these cells, and there should be distinct differences in the methods of internalization in the many cells where macropinocytosis is induced only by external stimuli. Our study suggests that macropinocytosis stimulates internalization of CXCR4 as well as viral uptake into late endosomes, which may decrease the chance of HIV entry into host cells via cell-surface fusion and promote viral degradation in endosomes (Schaeffer et al., 2001). "
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    ABSTRACT: CXCR4 is a coreceptor of HIV-1 infection in host cells. Through a photocrosslinking study to identify receptors involved in internalization of oligoarginine cell-penetrating peptides (CPPs), we found that CXCR4 serves as a receptor that stimulates macropinocytic uptake of the arginine 12-mer peptide (R12) but not of the 8-mer. We also found that stimulating CXCR4 with its intrinsic ligands, stromal cell-derived factor 1α and HIV-1 envelope glycoprotein 120, induced macropinocytosis. R12 had activity to prevent viral infection for HIV-1(IIIB), a subtype of HIV-1 that uses CXCR4 as a coreceptor for entry into susceptible cells, whereas the addition of a macropinocytosis inhibitor, dimethylamiloride, resulted in enhancement of viral infection. The present study shows that CXCR4 triggers macropinocytosis, which may have implications for the cellular uptake of oligoarginine CPPs and internalization of HIV.
    Full-text · Article · Nov 2012 · Chemistry & biology
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