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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.

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Nef enhances the expression levels of IFIT-1 mRNA in HIV-1-infected iDCs. The levels of IFIT-1 mRNA in iDCs mock infected or infected with WT NL(AD8) or NL(AD8)ΔNef were quantified using real-time RT-PCR. The IFIT-1 expression levels were normalized by the relative GAPDH expression levels. The results of mock-infected controls were assigned as 1 and the fold enhancement of IFIT-1 expression in HIV-1 infected iDCs is shown. WT, wild-type NL(AD8); ΔNef, NL(AD8)ΔNef. One representative experiment out of three is presented.
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Figure 9: Nef enhances the expression levels of IFIT-1 mRNA in HIV-1-infected iDCs. The levels of IFIT-1 mRNA in iDCs mock infected or infected with WT NL(AD8) or NL(AD8)ΔNef were quantified using real-time RT-PCR. The IFIT-1 expression levels were normalized by the relative GAPDH expression levels. The results of mock-infected controls were assigned as 1 and the fold enhancement of IFIT-1 expression in HIV-1 infected iDCs is shown. WT, wild-type NL(AD8); ΔNef, NL(AD8)ΔNef. One representative experiment out of three is presented.

Mentions: To explore the underlying mechanisms of Nef-dependent tetherin induction in HIV-1-infected iDCs, we quantified mRNA levels of IFIT-1, an IFN stimulated gene (ISG), in WT HIV-1 NL(AD8) or ΔNef-infected iDCs using real-time RT-PCR. Compared with mock infection, WT and ΔNef HIV-1 infections in iDCs resulted in a 5-fold increase of IFIT1 mRNA levels at 6 hr post-infection (Figure 9). At 16 and 48 hr post-infection, WT HIV-1 increased IFIT1 mRNA levels in infected iDCs 44- and 40-fold, respectively, relative to mock infection. By contrast, ΔNef HIV-1 infection in iDCs increased IFIT1 mRNA levels 13- and 27-fold at 16 and 48 hr post-infection, respectively, compared with mock infection (Figure 9). These data suggest that HIV-1 infection of iDCs induces ISG mRNA expression as an innate immune response, and that Nef plays an important role in this process.


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)

Nef enhances the expression levels of IFIT-1 mRNA in HIV-1-infected iDCs. The levels of IFIT-1 mRNA in iDCs mock infected or infected with WT NL(AD8) or NL(AD8)ΔNef were quantified using real-time RT-PCR. The IFIT-1 expression levels were normalized by the relative GAPDH expression levels. The results of mock-infected controls were assigned as 1 and the fold enhancement of IFIT-1 expression in HIV-1 infected iDCs is shown. WT, wild-type NL(AD8); ΔNef, NL(AD8)ΔNef. One representative experiment out of three is presented.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: Nef enhances the expression levels of IFIT-1 mRNA in HIV-1-infected iDCs. The levels of IFIT-1 mRNA in iDCs mock infected or infected with WT NL(AD8) or NL(AD8)ΔNef were quantified using real-time RT-PCR. The IFIT-1 expression levels were normalized by the relative GAPDH expression levels. The results of mock-infected controls were assigned as 1 and the fold enhancement of IFIT-1 expression in HIV-1 infected iDCs is shown. WT, wild-type NL(AD8); ΔNef, NL(AD8)ΔNef. One representative experiment out of three is presented.
Mentions: To explore the underlying mechanisms of Nef-dependent tetherin induction in HIV-1-infected iDCs, we quantified mRNA levels of IFIT-1, an IFN stimulated gene (ISG), in WT HIV-1 NL(AD8) or ΔNef-infected iDCs using real-time RT-PCR. Compared with mock infection, WT and ΔNef HIV-1 infections in iDCs resulted in a 5-fold increase of IFIT1 mRNA levels at 6 hr post-infection (Figure 9). At 16 and 48 hr post-infection, WT HIV-1 increased IFIT1 mRNA levels in infected iDCs 44- and 40-fold, respectively, relative to mock infection. By contrast, ΔNef HIV-1 infection in iDCs increased IFIT1 mRNA levels 13- and 27-fold at 16 and 48 hr post-infection, respectively, compared with mock infection (Figure 9). These data suggest that HIV-1 infection of iDCs induces ISG mRNA expression as an innate immune response, and that Nef plays an important role in this process.

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