Cell-to-cell HIV-1 spread and its implications for immune evasion

Martin, Neilson; Sattentau, Quentin J.

doi:10.1097/coh.0b013e328322f94a

Cited by 125 publications

(87 citation statements)

References 66 publications

(87 reference statements)

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“…It has been speculated that transfer of HIV-1 across VS may promote evasion from immune or therapeutic intervention with the inference that the junctions formed in retroviral VS may be nonpermissive to antibody entry (39). However, available evidence regarding whether neutralizing antibodies (NAb) and other entry inhibitors can inhibit HIV-1 cell-cell spread is inconsistent (25). An early analysis suggested that HIV-1 T-cell-T-cell spread is relatively resistant to neutralizing monoclonal antibodies (NMAb) (12).…”

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confidence: 99%

“…In parallel, viral Env and Gag are recruited to the interface by a microtubule-dependent mechanism (19), where polarized viral budding may release virions into the synaptic space across which the target cell is infected (17). The precise mechanism by which HIV-1 subsequently enters the target T-cell cytoplasm remains unclear: by fusion directly at the plasma membrane, fusion from within an endosomal compartment, or both (4,6,15,25,34).…”

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confidence: 99%

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

Martin

Welsch

Jolly

et al. 2010

J Virol

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174

280

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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.

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confidence: 99%

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confidence: 99%

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

Martin

Welsch

Jolly

et al. 2010

J Virol

Self Cite

174

280

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“…Cell-cell interactions (1,2) that play a critical role in normal immune system function are exploited by the virus to facilitate its transmission from antigenpresenting cells such as dendritic cells to susceptible target CD4 + T cells via a specialized structure designated a virological synapse (3,4). Although virological synapses can also be formed between uninfected and infected T cells (5)(6)(7), such synapses appear to be less tightly structured than synapses between dendritic cells and CD4 + T cells. Importantly, the transmission of virus to CD4 + T cells is far more efficient via a virological synapse than via cellfree diffusion (8).…”

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confidence: 99%

3D visualization of HIV transfer at the virological synapse between dendritic cells and T cells

Felts

Narayan

Estes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

169

176

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The efficiency of HIV infection is greatly enhanced when the virus is delivered at conjugates between CD4 + T cells and virus-bearing antigen-presenting cells such as macrophages or dendritic cells via specialized structures known as virological synapses. Using ion abrasion SEM, electron tomography, and superresolution light microscopy, we have analyzed the spatial architecture of cell-cell contacts and distribution of HIV virions at virological synapses formed between mature dendritic cells and T cells. We demonstrate the striking envelopment of T cells by sheet-like membrane extensions derived from mature dendritic cells, resulting in a shielded region for formation of virological synapses. Within the synapse, filopodial extensions emanating from CD4 + T cells make contact with HIV virions sequestered deep within a 3D network of surface-accessible compartments in the dendritic cell. Viruses are detected at the membrane surfaces of both dendritic cells and T cells, but virions are not released passively at the synapse; instead, virus transfer requires the engagement of T-cell CD4 receptors. The relative seclusion of T cells from the extracellular milieu, the burial of the site of HIV transfer, and the receptor-dependent initiation of virion transfer by T cells highlight unique aspects of cell-cell HIV transmission.

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“…Also, in vitro neutralizing antibodies from infected patients can neutralize cell-free HCV infection almost completely, whereas they fail to control infection in vivo (10)(11)(12). Likewise, other viruses, such as human T lymphotropic virus type 1 (HTLV-1) or HIV-1, use this type of transmission as their main mode of dissemination (13,14). HCV cell-to-cell transmission would serve as a fast mode of viral spread capable of facilitating viral evasion from the immune response (5), thus increasing pathogenesis.…”

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confidence: 99%

Apolipoprotein E, but Not Apolipoprotein B, Is Essential for Efficient Cell-to-Cell Transmission of Hepatitis C Virus

Gondar

Molina‐Jiménez

Hishiki

et al. 2015

J Virol

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Hepatitis C virus (HCV) infects hepatocytes through two different routes: (i) cell-free particle diffusion followed by engagement with specific cellular receptors and (ii) cell-to-cell direct transmission mediated by mechanisms not well defined yet. HCV exits host cells in association with very-low-density lipoprotein (VLDL) components. VLDL particles contain apolipoproteins B (ApoB) and E (ApoE), which are required for viral assembly and/or infectivity. Based on these precedents, we decided to study whether these VLDL components participate in HCV cell-to-cell transmission in vitro. We observed that cell-to-cell viral spread was compromised after ApoE interference in donor but not in acceptor cells. In contrast, ApoB knockdown in either donor or acceptor cells did not impair cell-to-cell viral transmission. Interestingly, ApoB participated in the assembly of cell-free infective virions, suggesting a differential regulation of cell-to-cell and cell-free HCV infection. This study identifies host-specific factors involved in these distinct routes of infection that may unveil new therapeutic targets and advance our understanding of HCV pathogenesis. IMPORTANCEThis work demonstrates that cell-to-cell transmission of HCV depends on ApoE but not ApoB. The data also indicate that ApoB is required for the assembly of cell-free infective particles, strongly suggesting the existence of mechanisms involving VLDL components that differentially regulate cell-free and cell-to-cell HCV transmission. These data clarify some of the questions regarding the role of VLDL in HCV pathogenesis and the transmission of the virus cell to cell as a possible mechanism of immune evasion and open the door to therapeutic intervention.

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Cell-to-cell HIV-1 spread and its implications for immune evasion

Abstract: The re-emergence of HIV-1 cell-cell spread as a highly efficient mechanism for viral dissemination in vitro has raised the possibility that this finding may be central to viral spread in vivo and may strongly influence pathogenesis.

Cited by 125 publications

References 66 publications

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

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

3D visualization of HIV transfer at the virological synapse between dendritic cells and T cells

Apolipoprotein E, but Not Apolipoprotein B, Is Essential for Efficient Cell-to-Cell Transmission of Hepatitis C Virus

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