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Asymmetric HIV-1 co-receptor use and replication in CD4(+) T lymphocytes.

Mariani SA, Vicenzi E, Poli G - J Transl Med (2011)

Bottom Line: In this regard, binding of the HIV-1 gp120 Env to the entry R complex, i.e. CD4 and a chemokine R, leads to two major events: virion-cell membrane fusion and a cascade of cell signaling.While the fusion/entry process has been well defined, the role of R/Co-R signaling in the HIV-1 life cycle has been less characterized.In this article, we will review the major findings related to the role of HIV R/Co-R signaling in the steps following viral entry and leading to viral spreading in CD4(+) T lymphocytes.

View Article: PubMed Central - HTML - PubMed

Affiliation: AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy.

ABSTRACT
Susceptibility to infection by the human immunodeficiency virus type-1 (HIV-1), both in vitro and in vivo, requires the interaction between its envelope (Env) glycoprotein gp120 Env and the primary receptor (R), CD4, and Co-R, either CCR5 or CXCR4, members of the chemokine receptor family. CCR5-dependent (R5) viruses are responsible for both inter-individual transmission and for sustaining the viral pandemics, while CXCR4-using viruses, usually dualtropic R5X4, emerge in ca. 50% of individuals only in the late, immunologically suppressed stage of disease. The hypothesis that such a major biological asymmetry is explained exclusively by the availability of cells expressing CCR5 or CXCR4 is challenged by several evidences. In this regard, binding of the HIV-1 gp120 Env to the entry R complex, i.e. CD4 and a chemokine R, leads to two major events: virion-cell membrane fusion and a cascade of cell signaling. While the fusion/entry process has been well defined, the role of R/Co-R signaling in the HIV-1 life cycle has been less characterized. Indeed, depending on the cellular model studied, the capacity of HIV-1 to trigger a flow of events favoring either its own latency or replication remains a debated issue. In this article, we will review the major findings related to the role of HIV R/Co-R signaling in the steps following viral entry and leading to viral spreading in CD4(+) T lymphocytes.

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Differential cell activation pathways triggered by R5 and X4 HIV-1 in CD4+ T cell. Both R5 and X4 HIV-1 gp120 Env engagement of CD4 and Co-R trigger signal transduction events leading to cell activation, host gene transcription, cell migration, survival and adhesion. R5 HIV-1 specifically induces adhesion via activation of FAK whereas X4 viruses modulate actin dynamics via activation of cofilin.
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Figure 2: Differential cell activation pathways triggered by R5 and X4 HIV-1 in CD4+ T cell. Both R5 and X4 HIV-1 gp120 Env engagement of CD4 and Co-R trigger signal transduction events leading to cell activation, host gene transcription, cell migration, survival and adhesion. R5 HIV-1 specifically induces adhesion via activation of FAK whereas X4 viruses modulate actin dynamics via activation of cofilin.

Mentions: An earlier study from our group looked at both polarized and unpolarized T cells of different origin, including classical Th1, Th2 or Th0 (unpolarized) T cell clones originated from adults peripheral blood or non-immortalized T cell lines derived from cord blood cells (particularly rich in naïve T cells) maintained for 14-20 days after polarization in medium containing IL-2 before exposure to R5 or X4 HIV-1. We have earlier observed that only R5, but not X4, HIV-1 efficiently replicated in both polarized and unpolarized T cell lines or clones in the face of the higher levels of expression of CXCR4 observed particularly in Th2 cells [53]. The lack of X4 HIV replication was not sustained by endogenous expression of CXCL12 and was reproduced with viruses derived from infectious molecular clones (pNLA4-3 and pNL-Ad8) sharing the same backbone except for the env-coding region, X4 and R5, respectively [53]. Of interest was the fact that infection by both R5 and X4 HIV-1 occurred with comparable efficiency in these primary cells up to 72 h post-infection when R5 viruses began to spread with an approximately 100-fold higher efficiency than X4 viruses [53]. However, re-stimulation of infected T cells by anti-CD3 mAb showed a dichotomous effect on R5 and X4 infections in that, on the one hand, strongly induced X4 HIV-1 replication, while, on the other hand, did not affect significantly the already efficient capacity of R5 viruses to propagate in these T cells [53]. We interpreted these results as suggestive of a superior capacity of CCR5 in delivering a cell-activating signal required for efficient HIV-1 spreading in T cells that is lacking when the cells are infected with an X4 virus (Figure 1). This interpretation is supported by earlier evidence showing that R5 gp120 Env trimers can deliver a qualitatively or quantitatively different signal to T cells resulting in Ca++-dependent signaling [54-56], as reviewed elsewhere in this issue. Indeed, Ca++-dependent signaling was earlier shown in different model systems to activate HIV expression in chronically infected cells [57] (Figure 2).


Asymmetric HIV-1 co-receptor use and replication in CD4(+) T lymphocytes.

Mariani SA, Vicenzi E, Poli G - J Transl Med (2011)

Differential cell activation pathways triggered by R5 and X4 HIV-1 in CD4+ T cell. Both R5 and X4 HIV-1 gp120 Env engagement of CD4 and Co-R trigger signal transduction events leading to cell activation, host gene transcription, cell migration, survival and adhesion. R5 HIV-1 specifically induces adhesion via activation of FAK whereas X4 viruses modulate actin dynamics via activation of cofilin.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105508&req=5

Figure 2: Differential cell activation pathways triggered by R5 and X4 HIV-1 in CD4+ T cell. Both R5 and X4 HIV-1 gp120 Env engagement of CD4 and Co-R trigger signal transduction events leading to cell activation, host gene transcription, cell migration, survival and adhesion. R5 HIV-1 specifically induces adhesion via activation of FAK whereas X4 viruses modulate actin dynamics via activation of cofilin.
Mentions: An earlier study from our group looked at both polarized and unpolarized T cells of different origin, including classical Th1, Th2 or Th0 (unpolarized) T cell clones originated from adults peripheral blood or non-immortalized T cell lines derived from cord blood cells (particularly rich in naïve T cells) maintained for 14-20 days after polarization in medium containing IL-2 before exposure to R5 or X4 HIV-1. We have earlier observed that only R5, but not X4, HIV-1 efficiently replicated in both polarized and unpolarized T cell lines or clones in the face of the higher levels of expression of CXCR4 observed particularly in Th2 cells [53]. The lack of X4 HIV replication was not sustained by endogenous expression of CXCL12 and was reproduced with viruses derived from infectious molecular clones (pNLA4-3 and pNL-Ad8) sharing the same backbone except for the env-coding region, X4 and R5, respectively [53]. Of interest was the fact that infection by both R5 and X4 HIV-1 occurred with comparable efficiency in these primary cells up to 72 h post-infection when R5 viruses began to spread with an approximately 100-fold higher efficiency than X4 viruses [53]. However, re-stimulation of infected T cells by anti-CD3 mAb showed a dichotomous effect on R5 and X4 infections in that, on the one hand, strongly induced X4 HIV-1 replication, while, on the other hand, did not affect significantly the already efficient capacity of R5 viruses to propagate in these T cells [53]. We interpreted these results as suggestive of a superior capacity of CCR5 in delivering a cell-activating signal required for efficient HIV-1 spreading in T cells that is lacking when the cells are infected with an X4 virus (Figure 1). This interpretation is supported by earlier evidence showing that R5 gp120 Env trimers can deliver a qualitatively or quantitatively different signal to T cells resulting in Ca++-dependent signaling [54-56], as reviewed elsewhere in this issue. Indeed, Ca++-dependent signaling was earlier shown in different model systems to activate HIV expression in chronically infected cells [57] (Figure 2).

Bottom Line: In this regard, binding of the HIV-1 gp120 Env to the entry R complex, i.e. CD4 and a chemokine R, leads to two major events: virion-cell membrane fusion and a cascade of cell signaling.While the fusion/entry process has been well defined, the role of R/Co-R signaling in the HIV-1 life cycle has been less characterized.In this article, we will review the major findings related to the role of HIV R/Co-R signaling in the steps following viral entry and leading to viral spreading in CD4(+) T lymphocytes.

View Article: PubMed Central - HTML - PubMed

Affiliation: AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy.

ABSTRACT
Susceptibility to infection by the human immunodeficiency virus type-1 (HIV-1), both in vitro and in vivo, requires the interaction between its envelope (Env) glycoprotein gp120 Env and the primary receptor (R), CD4, and Co-R, either CCR5 or CXCR4, members of the chemokine receptor family. CCR5-dependent (R5) viruses are responsible for both inter-individual transmission and for sustaining the viral pandemics, while CXCR4-using viruses, usually dualtropic R5X4, emerge in ca. 50% of individuals only in the late, immunologically suppressed stage of disease. The hypothesis that such a major biological asymmetry is explained exclusively by the availability of cells expressing CCR5 or CXCR4 is challenged by several evidences. In this regard, binding of the HIV-1 gp120 Env to the entry R complex, i.e. CD4 and a chemokine R, leads to two major events: virion-cell membrane fusion and a cascade of cell signaling. While the fusion/entry process has been well defined, the role of R/Co-R signaling in the HIV-1 life cycle has been less characterized. Indeed, depending on the cellular model studied, the capacity of HIV-1 to trigger a flow of events favoring either its own latency or replication remains a debated issue. In this article, we will review the major findings related to the role of HIV R/Co-R signaling in the steps following viral entry and leading to viral spreading in CD4(+) T lymphocytes.

Show MeSH
Related in: MedlinePlus