Limits...
Tetherin does not significantly restrict dendritic cell-mediated HIV-1 transmission and its expression is upregulated by newly synthesized HIV-1 Nef.

Coleman CM, Spearman P, Wu L - Retrovirology (2011)

Bottom Line: High levels of tetherin were transiently expressed in LPS- and IFNα-induced mature DCs, while HIV-1 localized into distinct patches in these DCs.Intriguingly, we found that HIV-1 replication in immature DCs induced significant tetherin expression in a Nef-dependent manner.Nef-dependent tetherin induction in HIV-1-infected immature DCs suggests an innate immune response of DCs to HIV-1 infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.

ABSTRACT

Background: Dendritic cells (DCs) are among the first cells to encounter HIV-1 and play important roles in viral transmission and pathogenesis. Immature DCs allow productive HIV-1 replication and long-term viral dissemination. The pro-inflammatory factor lipopolysaccharide (LPS) induces DC maturation and enhances the efficiency of DC-mediated HIV-1 transmission. Type I interferon (IFN) partially inhibits HIV-1 replication and cell-cell transmission in CD4+ T cells and macrophages. Tetherin is a type I IFN-inducible restriction factor that blocks HIV-1 release and modulates CD4+ T cell-mediated cell-to-cell transmission of HIV-1. However, the role of type I IFN and tetherin in HIV-1 infection of DCs and DC-mediated viral transmission remains unknown.

Results: We demonstrated that IFN-alpha (IFNα)-induced mature DCs restricted HIV-1 replication and trans-infection of CD4+ T cells. Tetherin expression in monocyte-derived immature DCs was undetectable or very low. High levels of tetherin were transiently expressed in LPS- and IFNα-induced mature DCs, while HIV-1 localized into distinct patches in these DCs. Knockdown of induced tetherin in LPS- or IFNα-matured DCs modestly enhanced HIV-1 transmission to CD4+ T cells, but had no significant effect on wild-type HIV-1 replication in mature DCs. Intriguingly, we found that HIV-1 replication in immature DCs induced significant tetherin expression in a Nef-dependent manner.

Conclusions: The restriction of HIV-1 replication and transmission in IFNα-induced mature DCs indicates a potent anti-HIV-1 response; however, high levels of tetherin induced in mature DCs cannot significantly restrict wild-type HIV-1 release and DC-mediated HIV-1 transmission. Nef-dependent tetherin induction in HIV-1-infected immature DCs suggests an innate immune response of DCs to HIV-1 infection.

Show MeSH

Related in: MedlinePlus

IFNα induces DC maturation but does not alter the expression of HIV-1 receptors. iDC, mDC-LPS and mDC-IFNα were stained for cell surface expression of CD4, CCR5, DC-SIGN and CD86. On each histogram, the filled peaks are the controls of isotype or secondary antibody alone and the black peaks represent the staining of specific markers. Top and bottom numbers shown in plots are % positive and the geometric mean values of fluorescence intensity, respectively. Results shown are from DCs from a single donor representative of two independent experiments on DCs from different donors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3108291&req=5

Figure 1: IFNα induces DC maturation but does not alter the expression of HIV-1 receptors. iDC, mDC-LPS and mDC-IFNα were stained for cell surface expression of CD4, CCR5, DC-SIGN and CD86. On each histogram, the filled peaks are the controls of isotype or secondary antibody alone and the black peaks represent the staining of specific markers. Top and bottom numbers shown in plots are % positive and the geometric mean values of fluorescence intensity, respectively. Results shown are from DCs from a single donor representative of two independent experiments on DCs from different donors.

Mentions: To examine the role of type I IFN in DC-mediated HIV-1 infection and transmission, human monocyte-derived iDCs were activated with IFNα to generate mature DCs (mDC-IFNα) and LPS-induced mature DCs (mDC-LPS) were used as positive controls. DCs were separately stained for surface CD86 as a marker of maturation [6,11,14,51], for the HIV-1 receptors CD4 and CCR5, and for the HIV-1 attachment factor DC-SIGN (DC-specific intercellular adhesion molecule-3 grabbing non-integrin). Maturation of DCs with either LPS or IFNα caused significant upregulation of CD86 expression on the cell surface by 6- to 7-fold (Figure 1), indicating that both mature DC types developed a mature DC phenotype. Compared with iDCs, mDC-IFNα did not show any significant differences in the expression of CD4, CCR5 or DC-SIGN, while mDC-LPS showed decreased levels of both CD4 and DC-SIGN (Figure 1). Surface CCR5 was equally expressed at low levels on all DC types (Figure 1). Thus, IFNα-induced maturation of DCs does not significantly affect the expression of HIV-1 receptors.


Tetherin does not significantly restrict dendritic cell-mediated HIV-1 transmission and its expression is upregulated by newly synthesized HIV-1 Nef.

Coleman CM, Spearman P, Wu L - Retrovirology (2011)

IFNα induces DC maturation but does not alter the expression of HIV-1 receptors. iDC, mDC-LPS and mDC-IFNα were stained for cell surface expression of CD4, CCR5, DC-SIGN and CD86. On each histogram, the filled peaks are the controls of isotype or secondary antibody alone and the black peaks represent the staining of specific markers. Top and bottom numbers shown in plots are % positive and the geometric mean values of fluorescence intensity, respectively. Results shown are from DCs from a single donor representative of two independent experiments on DCs from different donors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108291&req=5

Figure 1: IFNα induces DC maturation but does not alter the expression of HIV-1 receptors. iDC, mDC-LPS and mDC-IFNα were stained for cell surface expression of CD4, CCR5, DC-SIGN and CD86. On each histogram, the filled peaks are the controls of isotype or secondary antibody alone and the black peaks represent the staining of specific markers. Top and bottom numbers shown in plots are % positive and the geometric mean values of fluorescence intensity, respectively. Results shown are from DCs from a single donor representative of two independent experiments on DCs from different donors.
Mentions: To examine the role of type I IFN in DC-mediated HIV-1 infection and transmission, human monocyte-derived iDCs were activated with IFNα to generate mature DCs (mDC-IFNα) and LPS-induced mature DCs (mDC-LPS) were used as positive controls. DCs were separately stained for surface CD86 as a marker of maturation [6,11,14,51], for the HIV-1 receptors CD4 and CCR5, and for the HIV-1 attachment factor DC-SIGN (DC-specific intercellular adhesion molecule-3 grabbing non-integrin). Maturation of DCs with either LPS or IFNα caused significant upregulation of CD86 expression on the cell surface by 6- to 7-fold (Figure 1), indicating that both mature DC types developed a mature DC phenotype. Compared with iDCs, mDC-IFNα did not show any significant differences in the expression of CD4, CCR5 or DC-SIGN, while mDC-LPS showed decreased levels of both CD4 and DC-SIGN (Figure 1). Surface CCR5 was equally expressed at low levels on all DC types (Figure 1). Thus, IFNα-induced maturation of DCs does not significantly affect the expression of HIV-1 receptors.

Bottom Line: High levels of tetherin were transiently expressed in LPS- and IFNα-induced mature DCs, while HIV-1 localized into distinct patches in these DCs.Intriguingly, we found that HIV-1 replication in immature DCs induced significant tetherin expression in a Nef-dependent manner.Nef-dependent tetherin induction in HIV-1-infected immature DCs suggests an innate immune response of DCs to HIV-1 infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.

ABSTRACT

Background: Dendritic cells (DCs) are among the first cells to encounter HIV-1 and play important roles in viral transmission and pathogenesis. Immature DCs allow productive HIV-1 replication and long-term viral dissemination. The pro-inflammatory factor lipopolysaccharide (LPS) induces DC maturation and enhances the efficiency of DC-mediated HIV-1 transmission. Type I interferon (IFN) partially inhibits HIV-1 replication and cell-cell transmission in CD4+ T cells and macrophages. Tetherin is a type I IFN-inducible restriction factor that blocks HIV-1 release and modulates CD4+ T cell-mediated cell-to-cell transmission of HIV-1. However, the role of type I IFN and tetherin in HIV-1 infection of DCs and DC-mediated viral transmission remains unknown.

Results: We demonstrated that IFN-alpha (IFNα)-induced mature DCs restricted HIV-1 replication and trans-infection of CD4+ T cells. Tetherin expression in monocyte-derived immature DCs was undetectable or very low. High levels of tetherin were transiently expressed in LPS- and IFNα-induced mature DCs, while HIV-1 localized into distinct patches in these DCs. Knockdown of induced tetherin in LPS- or IFNα-matured DCs modestly enhanced HIV-1 transmission to CD4+ T cells, but had no significant effect on wild-type HIV-1 replication in mature DCs. Intriguingly, we found that HIV-1 replication in immature DCs induced significant tetherin expression in a Nef-dependent manner.

Conclusions: The restriction of HIV-1 replication and transmission in IFNα-induced mature DCs indicates a potent anti-HIV-1 response; however, high levels of tetherin induced in mature DCs cannot significantly restrict wild-type HIV-1 release and DC-mediated HIV-1 transmission. Nef-dependent tetherin induction in HIV-1-infected immature DCs suggests an innate immune response of DCs to HIV-1 infection.

Show MeSH
Related in: MedlinePlus