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HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse.

Jolly C, Kashefi K, Hollinshead M, Sattentau QJ - J. Exp. Med. (2004)

Bottom Line: Receptor recognition by HIV-1 occurs via interactions between the viral surface envelope glycoprotein (Env), gp120, and CD4 and a chemokine receptor, CCR5 or CXCR4.Recruitment of these membrane molecules into polarized clusters was dependent on Env engagement of CD4 and CXCR4 and required remodelling of the actin cytoskeleton.We propose that receptor engagement by Env directs the rapid, actin-dependent recruitment of HIV receptors and adhesion molecules to the interface, resulting in a stable adhesive junction across which HIV infects the target cell.

View Article: PubMed Central - PubMed

Affiliation: The Sir William Dunn School of Pathology, University of Oxford, UK.

ABSTRACT
Direct cell-cell transfer is an efficient mechanism of viral dissemination within an infected host, and human immunodeficiency virus 1 (HIV-1) can exploit this mode of spread. Receptor recognition by HIV-1 occurs via interactions between the viral surface envelope glycoprotein (Env), gp120, and CD4 and a chemokine receptor, CCR5 or CXCR4. Here, we demonstrate that the binding of CXCR4-using HIV-1-infected effector T cells to primary CD4(+)/CXCR4(+) target T cells results in rapid recruitment to the interface of CD4, CXCR4, talin, and lymphocyte function-associated antigen 1 on the target cell, and of Env and Gag on the effector cell. Recruitment of these membrane molecules into polarized clusters was dependent on Env engagement of CD4 and CXCR4 and required remodelling of the actin cytoskeleton. Transfer of Gag from effector to target cell was observed by 1 h after conjugate formation, was independent of cell-cell fusion, and was probably mediated by directed virion fusion with the target cell. We propose that receptor engagement by Env directs the rapid, actin-dependent recruitment of HIV receptors and adhesion molecules to the interface, resulting in a stable adhesive junction across which HIV infects the target cell.

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Related in: MedlinePlus

Talin and LFA-1 cluster at the target–effector cell interface. Conjugates between effector and target cells formed for 1 h at 37°C were stained for Env with 50-69 (green). The target cell was identified using a CD4-specific rabbit polyclonal serum (staining not depicted) and is indicated with an arrow. (A) Conjugates were either fixed with prechilled methanol and stained for the actin adaptor protein talin (red), (B) stained for the integrin LFA-1, or (C) CD3 before fixing in formaldehyde.
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fig2: Talin and LFA-1 cluster at the target–effector cell interface. Conjugates between effector and target cells formed for 1 h at 37°C were stained for Env with 50-69 (green). The target cell was identified using a CD4-specific rabbit polyclonal serum (staining not depicted) and is indicated with an arrow. (A) Conjugates were either fixed with prechilled methanol and stained for the actin adaptor protein talin (red), (B) stained for the integrin LFA-1, or (C) CD3 before fixing in formaldehyde.

Mentions: Interactions between the adhesion molecules LFA-1 and ICAM-1 increase HIV-1 infection and syncytium formation. Moreover, these interactions create an adhesive patch in immune cell interactions, which are intrinsic to formation of the immunological synapse (29). Therefore, we hypothesized that in a manner similar to the formation of an immunological synapse, LFA-1 might be recruited to the target–effector cell interface. We investigated the localization of the actin anchor protein talin and the associated integrin LFA-1 in conjugates. At 30 min, talin was observed in discrete microclusters at the interface of ∼16% of conjugates, frequently forming partial ringlike structures (Fig. 2 A and unpublished data). LFA-1 was tightly associated with the interface and colocalized with Env (Fig. 2 B); because JurkatLAI express little LFA-1, the clustering was clearly taking place on the target cell. No clustering of talin or LFA-1 was observed on target cells in conjugates with uninfected Jurkats (unpublished data).


HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse.

Jolly C, Kashefi K, Hollinshead M, Sattentau QJ - J. Exp. Med. (2004)

Talin and LFA-1 cluster at the target–effector cell interface. Conjugates between effector and target cells formed for 1 h at 37°C were stained for Env with 50-69 (green). The target cell was identified using a CD4-specific rabbit polyclonal serum (staining not depicted) and is indicated with an arrow. (A) Conjugates were either fixed with prechilled methanol and stained for the actin adaptor protein talin (red), (B) stained for the integrin LFA-1, or (C) CD3 before fixing in formaldehyde.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211771&req=5

fig2: Talin and LFA-1 cluster at the target–effector cell interface. Conjugates between effector and target cells formed for 1 h at 37°C were stained for Env with 50-69 (green). The target cell was identified using a CD4-specific rabbit polyclonal serum (staining not depicted) and is indicated with an arrow. (A) Conjugates were either fixed with prechilled methanol and stained for the actin adaptor protein talin (red), (B) stained for the integrin LFA-1, or (C) CD3 before fixing in formaldehyde.
Mentions: Interactions between the adhesion molecules LFA-1 and ICAM-1 increase HIV-1 infection and syncytium formation. Moreover, these interactions create an adhesive patch in immune cell interactions, which are intrinsic to formation of the immunological synapse (29). Therefore, we hypothesized that in a manner similar to the formation of an immunological synapse, LFA-1 might be recruited to the target–effector cell interface. We investigated the localization of the actin anchor protein talin and the associated integrin LFA-1 in conjugates. At 30 min, talin was observed in discrete microclusters at the interface of ∼16% of conjugates, frequently forming partial ringlike structures (Fig. 2 A and unpublished data). LFA-1 was tightly associated with the interface and colocalized with Env (Fig. 2 B); because JurkatLAI express little LFA-1, the clustering was clearly taking place on the target cell. No clustering of talin or LFA-1 was observed on target cells in conjugates with uninfected Jurkats (unpublished data).

Bottom Line: Receptor recognition by HIV-1 occurs via interactions between the viral surface envelope glycoprotein (Env), gp120, and CD4 and a chemokine receptor, CCR5 or CXCR4.Recruitment of these membrane molecules into polarized clusters was dependent on Env engagement of CD4 and CXCR4 and required remodelling of the actin cytoskeleton.We propose that receptor engagement by Env directs the rapid, actin-dependent recruitment of HIV receptors and adhesion molecules to the interface, resulting in a stable adhesive junction across which HIV infects the target cell.

View Article: PubMed Central - PubMed

Affiliation: The Sir William Dunn School of Pathology, University of Oxford, UK.

ABSTRACT
Direct cell-cell transfer is an efficient mechanism of viral dissemination within an infected host, and human immunodeficiency virus 1 (HIV-1) can exploit this mode of spread. Receptor recognition by HIV-1 occurs via interactions between the viral surface envelope glycoprotein (Env), gp120, and CD4 and a chemokine receptor, CCR5 or CXCR4. Here, we demonstrate that the binding of CXCR4-using HIV-1-infected effector T cells to primary CD4(+)/CXCR4(+) target T cells results in rapid recruitment to the interface of CD4, CXCR4, talin, and lymphocyte function-associated antigen 1 on the target cell, and of Env and Gag on the effector cell. Recruitment of these membrane molecules into polarized clusters was dependent on Env engagement of CD4 and CXCR4 and required remodelling of the actin cytoskeleton. Transfer of Gag from effector to target cell was observed by 1 h after conjugate formation, was independent of cell-cell fusion, and was probably mediated by directed virion fusion with the target cell. We propose that receptor engagement by Env directs the rapid, actin-dependent recruitment of HIV receptors and adhesion molecules to the interface, resulting in a stable adhesive junction across which HIV infects the target cell.

Show MeSH
Related in: MedlinePlus