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How to engage Cofilin.

Bukrinsky M - Retrovirology (2008)

Bottom Line: Still, we do not have a complete understanding of the factors regulating HIV replication in these cells.As a result of this activation, actin is depolymerized, thus destroying the natural barrier to HIV replication.I discuss implications of this study for our understanding of HIV biology and development of novel anti-HIV therapeutic approaches.

View Article: PubMed Central - HTML - PubMed

Affiliation: George Washington University, Department of Microbiology, Immunology and Tropical Medicine, Washington, DC 20037, USA. mtmmib@gwumc.edu

ABSTRACT
In HIV-infected people, resting CD4+ T cells are the main reservoir of latent virus and the reason for the failure of drug therapy to cure HIV infection. Still, we do not have a complete understanding of the factors regulating HIV replication in these cells. A recent paper in Cell describes a new trick that the virus uses to infect resting T cells. Interaction between the viral gp120 and cellular HIV co-receptor, CXCR4, during viral entry initiates signaling that activates cofilin, the main regulator of actin polymerization. As a result of this activation, actin is depolymerized, thus destroying the natural barrier to HIV replication. I discuss implications of this study for our understanding of HIV biology and development of novel anti-HIV therapeutic approaches.

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Related in: MedlinePlus

A model depicting actin regulation by cofilin during HIV-1 infection of resting T cell. Interactions between the key factors involved in regulation of cortical actin are shown in the context of HIV-1 infection. HIV-induced signaling from CXCR4 activates phosphatase which dephosphorylates and activates cofilin. This leads to depolymerization of F-actin, releasing HIV-1 reverse transcription complex and promoting its translocation towards the nucleus. Steps requiring additional studies, such as involvement of CCR5 in cofilin activation, regulation of a switch between activation of cofilin kinase and phosphatase, the role of F-actin in HIV reverse transcription and nuclear translocation are marked by question marks. See text for details.
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Figure 1: A model depicting actin regulation by cofilin during HIV-1 infection of resting T cell. Interactions between the key factors involved in regulation of cortical actin are shown in the context of HIV-1 infection. HIV-induced signaling from CXCR4 activates phosphatase which dephosphorylates and activates cofilin. This leads to depolymerization of F-actin, releasing HIV-1 reverse transcription complex and promoting its translocation towards the nucleus. Steps requiring additional studies, such as involvement of CCR5 in cofilin activation, regulation of a switch between activation of cofilin kinase and phosphatase, the role of F-actin in HIV reverse transcription and nuclear translocation are marked by question marks. See text for details.

Mentions: So what is the nature of this compartment? An intriguing observation reported by Yoder et al. is that HIV-induced CXCR4-dependent signaling triggers rapid polymerization and subsequent depolymerization of the cortical actin filaments (Fig. 1). Actin polymerization is an essential mechanism of chemotactic cell motility induced by chemokines [18], and has been documented for CXCR4-dependent T cell chemotaxis in response to SDF-1 or gp120 stimulation [19,20]. An unexpected finding by Yoder et al. is HIV-induced rapid depolymerization of polymerized actin (F-actin). When actin depolymerization was blocked by actin-stabilizing agent. jasplakinolide, HIV replication following cell activation was inhibited. This result suggests that actin depolymerization is critical for HIV replication. Previously, association of incoming HIV with F-actin was proposed to be a necessary step in formation of the reverse transcription complex and reverse transcription [21]. It now appears that this association has to be very transient, and if not disrupted within 5 minutes after infection by actin depolymerization, it will prevent subsequent steps of HIV replication. It remains to be determined what happens to the viral reverse transcription complex during the first 5 minutes after entry and why this first time period is so critical for subsequent replication.


How to engage Cofilin.

Bukrinsky M - Retrovirology (2008)

A model depicting actin regulation by cofilin during HIV-1 infection of resting T cell. Interactions between the key factors involved in regulation of cortical actin are shown in the context of HIV-1 infection. HIV-induced signaling from CXCR4 activates phosphatase which dephosphorylates and activates cofilin. This leads to depolymerization of F-actin, releasing HIV-1 reverse transcription complex and promoting its translocation towards the nucleus. Steps requiring additional studies, such as involvement of CCR5 in cofilin activation, regulation of a switch between activation of cofilin kinase and phosphatase, the role of F-actin in HIV reverse transcription and nuclear translocation are marked by question marks. See text for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2567344&req=5

Figure 1: A model depicting actin regulation by cofilin during HIV-1 infection of resting T cell. Interactions between the key factors involved in regulation of cortical actin are shown in the context of HIV-1 infection. HIV-induced signaling from CXCR4 activates phosphatase which dephosphorylates and activates cofilin. This leads to depolymerization of F-actin, releasing HIV-1 reverse transcription complex and promoting its translocation towards the nucleus. Steps requiring additional studies, such as involvement of CCR5 in cofilin activation, regulation of a switch between activation of cofilin kinase and phosphatase, the role of F-actin in HIV reverse transcription and nuclear translocation are marked by question marks. See text for details.
Mentions: So what is the nature of this compartment? An intriguing observation reported by Yoder et al. is that HIV-induced CXCR4-dependent signaling triggers rapid polymerization and subsequent depolymerization of the cortical actin filaments (Fig. 1). Actin polymerization is an essential mechanism of chemotactic cell motility induced by chemokines [18], and has been documented for CXCR4-dependent T cell chemotaxis in response to SDF-1 or gp120 stimulation [19,20]. An unexpected finding by Yoder et al. is HIV-induced rapid depolymerization of polymerized actin (F-actin). When actin depolymerization was blocked by actin-stabilizing agent. jasplakinolide, HIV replication following cell activation was inhibited. This result suggests that actin depolymerization is critical for HIV replication. Previously, association of incoming HIV with F-actin was proposed to be a necessary step in formation of the reverse transcription complex and reverse transcription [21]. It now appears that this association has to be very transient, and if not disrupted within 5 minutes after infection by actin depolymerization, it will prevent subsequent steps of HIV replication. It remains to be determined what happens to the viral reverse transcription complex during the first 5 minutes after entry and why this first time period is so critical for subsequent replication.

Bottom Line: Still, we do not have a complete understanding of the factors regulating HIV replication in these cells.As a result of this activation, actin is depolymerized, thus destroying the natural barrier to HIV replication.I discuss implications of this study for our understanding of HIV biology and development of novel anti-HIV therapeutic approaches.

View Article: PubMed Central - HTML - PubMed

Affiliation: George Washington University, Department of Microbiology, Immunology and Tropical Medicine, Washington, DC 20037, USA. mtmmib@gwumc.edu

ABSTRACT
In HIV-infected people, resting CD4+ T cells are the main reservoir of latent virus and the reason for the failure of drug therapy to cure HIV infection. Still, we do not have a complete understanding of the factors regulating HIV replication in these cells. A recent paper in Cell describes a new trick that the virus uses to infect resting T cells. Interaction between the viral gp120 and cellular HIV co-receptor, CXCR4, during viral entry initiates signaling that activates cofilin, the main regulator of actin polymerization. As a result of this activation, actin is depolymerized, thus destroying the natural barrier to HIV replication. I discuss implications of this study for our understanding of HIV biology and development of novel anti-HIV therapeutic approaches.

Show MeSH
Related in: MedlinePlus