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

HIV-1 localizes with CD81 and tetherin in mature DCs. Localization of HIV-1 with cellular markers within mature DCs was assessed by confocal microscopy. (A) Representative confocal images of localization characteristics of HIV-GFP-Vpr in mDC-LPS; HIV-GFP-Vpr co-localizes with CD81 and tetherin, but not LAMP-1 in mDC-LPS. (B) Pearson's correlation coefficient analysis of mDC-LPS images. (C) Representative confocal images of localization characteristics of HIV-GFP-Vpr in mDC-IFNα; HIV-GFP-Vpr co-localizes with CD81 and tetherin, but not LAMP-1 in mDC- IFNα. (D) Pearson's correlation coefficient analysis of mDC-IFNα images. Numbers on graphic bars indicate the number of cells analyzed. Data presented are the mean ± SEM. Scale bars are 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: HIV-1 localizes with CD81 and tetherin in mature DCs. Localization of HIV-1 with cellular markers within mature DCs was assessed by confocal microscopy. (A) Representative confocal images of localization characteristics of HIV-GFP-Vpr in mDC-LPS; HIV-GFP-Vpr co-localizes with CD81 and tetherin, but not LAMP-1 in mDC-LPS. (B) Pearson's correlation coefficient analysis of mDC-LPS images. (C) Representative confocal images of localization characteristics of HIV-GFP-Vpr in mDC-IFNα; HIV-GFP-Vpr co-localizes with CD81 and tetherin, but not LAMP-1 in mDC- IFNα. (D) Pearson's correlation coefficient analysis of mDC-IFNα images. Numbers on graphic bars indicate the number of cells analyzed. Data presented are the mean ± SEM. Scale bars are 10 μm.

Mentions: Consistent with previous reports [12,57,58], HIV-GFP-Vpr localized into an intense patch with CD81 and did not co-localize with LAMP-1 in mDC-LPS (Figure 4A), which was confirmed by the correlation analysis of co-localization (Figure 4B). Furthermore, the intense patch of HIV-1 observed in mDC-LPS co-localized with tetherin (Figure 4A) and the correlation analysis confirmed the co-localization (Figure 4B). In mDC-IFNα, HIV-GFP-Vpr localized into smaller patches near the plasma membrane (Figure 4C) and showed co-localization with CD81 (Figure 4C), with the correlation coefficient being similar to that observed in mDC-LPS (Figure 4B and 4D). HIV-Vpr-GFP did not co-localize with LAMP-1 in mDC-IFNα (Figure 4C) and the correlation coefficient was very low (Figure 4D). The punctate patches of HIV-1 in mDC-IFNα appeared to localize with tetherin (Figure 4C and 4D). These data indicate that in mDC-IFNα and mDC-LPS, HIV-1 localizes into distinct patches that co-localize with CD81 and tetherin but not with LAMP-1. These results suggest that LPS- and IFNα-induced tetherin expression may affect HIV-1 trafficking and transmission in mature DCs.


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)

HIV-1 localizes with CD81 and tetherin in mature DCs. Localization of HIV-1 with cellular markers within mature DCs was assessed by confocal microscopy. (A) Representative confocal images of localization characteristics of HIV-GFP-Vpr in mDC-LPS; HIV-GFP-Vpr co-localizes with CD81 and tetherin, but not LAMP-1 in mDC-LPS. (B) Pearson's correlation coefficient analysis of mDC-LPS images. (C) Representative confocal images of localization characteristics of HIV-GFP-Vpr in mDC-IFNα; HIV-GFP-Vpr co-localizes with CD81 and tetherin, but not LAMP-1 in mDC- IFNα. (D) Pearson's correlation coefficient analysis of mDC-IFNα images. Numbers on graphic bars indicate the number of cells analyzed. Data presented are the mean ± SEM. Scale bars are 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: HIV-1 localizes with CD81 and tetherin in mature DCs. Localization of HIV-1 with cellular markers within mature DCs was assessed by confocal microscopy. (A) Representative confocal images of localization characteristics of HIV-GFP-Vpr in mDC-LPS; HIV-GFP-Vpr co-localizes with CD81 and tetherin, but not LAMP-1 in mDC-LPS. (B) Pearson's correlation coefficient analysis of mDC-LPS images. (C) Representative confocal images of localization characteristics of HIV-GFP-Vpr in mDC-IFNα; HIV-GFP-Vpr co-localizes with CD81 and tetherin, but not LAMP-1 in mDC- IFNα. (D) Pearson's correlation coefficient analysis of mDC-IFNα images. Numbers on graphic bars indicate the number of cells analyzed. Data presented are the mean ± SEM. Scale bars are 10 μm.
Mentions: Consistent with previous reports [12,57,58], HIV-GFP-Vpr localized into an intense patch with CD81 and did not co-localize with LAMP-1 in mDC-LPS (Figure 4A), which was confirmed by the correlation analysis of co-localization (Figure 4B). Furthermore, the intense patch of HIV-1 observed in mDC-LPS co-localized with tetherin (Figure 4A) and the correlation analysis confirmed the co-localization (Figure 4B). In mDC-IFNα, HIV-GFP-Vpr localized into smaller patches near the plasma membrane (Figure 4C) and showed co-localization with CD81 (Figure 4C), with the correlation coefficient being similar to that observed in mDC-LPS (Figure 4B and 4D). HIV-Vpr-GFP did not co-localize with LAMP-1 in mDC-IFNα (Figure 4C) and the correlation coefficient was very low (Figure 4D). The punctate patches of HIV-1 in mDC-IFNα appeared to localize with tetherin (Figure 4C and 4D). These data indicate that in mDC-IFNα and mDC-LPS, HIV-1 localizes into distinct patches that co-localize with CD81 and tetherin but not with LAMP-1. These results suggest that LPS- and IFNα-induced tetherin expression may affect HIV-1 trafficking and transmission in mature DCs.

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