Trans-infection but Not Infection from within Endosomal Compartments after Cell-to-cell HIV-1 Transfer to CD4+ T Cells

Permanyer, Marc; Ballana, Ester; Badía, Roger; Pauls, Eduardo; Clotet, Bonaventura; Esté, José A.

doi:10.1074/jbc.m112.343293

Cited by 12 publications

(16 citation statements)

References 43 publications

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“…In vitro studies of the evolution of drug resistance have reached similar conclusions, i.e., resistance may be more common following cell-cell transmission. In support of this, our data here and the results of others [ 33 , 42 , 43 ] have shown that entry inhibitors can inhibit HIV cell-cell spread but only at much higher concentrations than are effective at blocking cell-free transmission.…”

Section: Discussionsupporting

confidence: 91%

Identification of an env-defective HIV-1 mutant capable of spontaneous reversion to a wild-type phenotype in certain T-cell lines

Quan

Kramer

et al. 2014

Virol J

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BackgroundAttempts to eradicate HIV from cellular reservoirs are vital but depend on a clear understanding of how viral variants are transmitted and survive in the different cell types that constitute such reservoirs. Mutations in the env gene of HIV may be able to exert a differential influence on viral transmission ability in regard to cell-free and cell-associated viral forms.MethodsThe ability of HIV containing an env G367R mutation in cell-free and cell-associated viruses to cause infection and to revert to wild-type was measured using several T cell lines. To determine factors that might potentially influence the reversion of G367R, we studied each of entry inhibitors, inhibitors of cellular endocytosis, and modulators of cell growth and activation.ResultsWe demonstrate that an HIV-1 variant containing a G367R substitution within the CD4 binding site of gp120 was non-infectious as free virus in culture but was infectious when infected cells were co-cultured with certain T cell lines or when cells were transfected by a relevant proviral plasmid. Differences in viral infectivity by cell-associated G367R viruses were determined by the type of target cell employed, regardless which type of donor cell was used. Reversion was slowed or inhibited by entry inhibitors and by inhibitors of cellular endocytosis. Interleukin 2 was able to block G367R reversion in only one of the T cell lines studied but not in the other, while phorbol 12-myristate 13-acetate (PMA) inhibited G367R reversion in all the T cell lines.ConclusionsEnv-defective HIV may have a different phenotype as cell-free versus cell-associated virus. The persistence of defective forms can potentially lead to the emergence of virulent forms. The heterogeneity of cell types that constitute the HIV reservoir can contribute to viral variability, even among similar types of cells. This is the first demonstration of a mutation in the HIV envelope, i.e. G367R, that can compromise infection by cell-free virus but less severely by cell-associated virus and that does so in a cell type-dependent manner.

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Section: Discussionsupporting

confidence: 91%

Identification of an env-defective HIV-1 mutant capable of spontaneous reversion to a wild-type phenotype in certain T-cell lines

Quan

Kramer

et al. 2014

Virol J

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“…In agreement with prior studies with HSV-1 and other viruses, including Chikungunya virus (31), Japanese encephalitis virus (32), reoviruses (33), Ebola virus (34), and HIV (with HaCaT cells but not primary CD4 T cells) (29,35,36), dynasore inhibited the entry of HSV-1 and HSV-2 into human neuronal (SK-N-SH and fetal primary) and genital tract (CaSki and primary) cells. Entry was defined here as the successful transport of tegument (VP16) or capsid (VP26-GFP) proteins to the nuclear pore; thus, the inhibitory activity may reflect interference with one of several entry mechanisms, such as endocytosis or macropinocytosis and/or a block in capsid transport along the microtubular network.…”

Section: Discussionsupporting

confidence: 90%

Dynasore Disrupts Trafficking of Herpes Simplex Virus Proteins

Mues

Cheshenko

Wilson

et al. 2015

J Virol

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Dynasore, a small-molecule inhibitor of the GTPase activity of dynamin, inhibits the entry of several viruses, including herpes simplex virus (HSV), but its impact on other steps in the viral life cycle has not been delineated. The current study was designed to test the hypothesis that dynamin is required for viral protein trafficking and thus has pleiotropic inhibitory effects on HSV infection. Dynasore inhibited HSV-1 and HSV-2 infection of human epithelial and neuronal cells, including primary genital tract cells and human fetal neurons and astrocytes. Similar results were obtained when cells were transfected with a plasmid expressing dominant negative dynamin. Kinetic studies demonstrated that dynasore reduced the number of viral capsids reaching the nuclear pore if added at the time of viral entry and that, when added as late as 8 h postentry, dynasore blocked the transport of newly synthesized viral proteins from the nucleus to the cytosol. Proximity ligation assays demonstrated that treatment with dynasore prevented the colocalization of VP5 and dynamin. This resulted in a reduction in the number of viral capsids isolated from sucrose gradients. Fewer capsids were observed by electron microscopy in dynasore-treated cells than in control-treated cells. There were also reductions in infectious progeny released into culture supernatants and in cell-to-cell spread. Together, these findings suggest that targeting dynamin-HSV interactions may provide a new strategy for HSV treatment and prevention. IMPORTANCEHSV infections remain a global health problem associated with significant morbidity, particularly in neonates and immunocompromised hosts, highlighting the need for novel approaches to treatment and prevention. The current studies indicate that dynamin plays a role in multiple steps in the viral life cycle and provides a new target for antiviral therapy. Dynasore, a small-molecule inhibitor of dynamin, has pleiotropic effects on HSV-1 and HSV-2 infection and impedes viral entry, trafficking of viral proteins, and capsid formation.

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“…Cells were stained with CD4, CXCR4 (12G5) or CD45RA antibodies (BD Biosciences). Intracellular staining of HIV-1 p24 antigen (CAp24) was performed as previously described [22] , [31] – [33] . Briefly, cells were fixed, permeabilized (Fix & Perm, Caltag, Burlingame, CA) and stained with the anti-HIV-CAp24 antigen mAb KC57 (Coulter, Barcelona, Spain).…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, cortical actin dynamics is also required during cell-to-cell HIV transmission by promoting the concentration of HIV antigens and its cellular receptors at the cell-cell contact zone [21] . Moreover, the uptake of HIV antigens into endocytic compartments after cell-to-cell transfer [22] – [25] could be prevented by pharmacological disruption of the cortical actin of effector cells [24] , [26] , [27] , suggesting that active cytoskeleton dynamics is required for the internalization process. However, the role of the cytoskeleton during cell-to-cell HIV transmission into distinct T cells subsets has not been well characterized.…”

Section: Introductionmentioning

confidence: 99%

The Cortical Actin Determines Different Susceptibility of Naïve and Memory CD4+ T Cells to HIV-1 Cell-to-Cell Transmission and Infection

et al. 2013

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Memory CD4+ T cells are preferentially infected by HIV-1 compared to naïve cells. HIV-1 fusion and entry is a dynamic process in which the cytoskeleton plays an important role by allowing virion internalization and uncoating. Here, we evaluate the role of the cortical actin in cell-to-cell transfer of virus antigens and infection of target CD4+ T cells. Using different actin remodeling compounds we demonstrate that efficiency of HIV-internalization was proportional to the actin polymerization of the target cell. Naïve (CD45RA+) and memory (CD45RA−) CD4+ T cells could be phenotypically differentiated by the degree of cortical actin density and their capacity to capture virus. Thus, the higher cortical actin density of memory CD4+ T cells was associated to increased efficiency of HIV-antigen internalization and the establishment of a productive infection. Conversely, the lower cortical actin density in naïve CD4+ T cells restricted viral antigen transfer and consequently HIV-1 infection. In conclusion, the cortical actin density differentially affects the susceptibility to HIV-1 infection in naïve and memory CD4+ T cells by modulating the efficiency of HIV antigen internalization.

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Trans-infection but Not Infection from within Endosomal Compartments after Cell-to-cell HIV-1 Transfer to CD4+ T Cells

Cited by 12 publications

References 43 publications

Identification of an env-defective HIV-1 mutant capable of spontaneous reversion to a wild-type phenotype in certain T-cell lines

Identification of an env-defective HIV-1 mutant capable of spontaneous reversion to a wild-type phenotype in certain T-cell lines

Dynasore Disrupts Trafficking of Herpes Simplex Virus Proteins

The Cortical Actin Determines Different Susceptibility of Naïve and Memory CD4+ T Cells to HIV-1 Cell-to-Cell Transmission and Infection

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