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Increased BST2 expression during simian immunodeficiency virus infection is not a determinant of disease progression in rhesus monkeys.

Mussil B, Javed A, Töpfer K, Sauermann U, Sopper S - Retrovirology (2015)

Bottom Line: Highest BST2 levels were found in progressors and lowest levels comparable to uninfected macaques were observed in long-term non-progressors (LTNPs).During acute viremia, BST2 mRNA increased in parallel with MX1, a prototype interferon-stimulated gene.This association was maintained during the whole disease course.

View Article: PubMed Central - PubMed

Affiliation: Unit of Infection Models, German Primate Centre, Goettingen, Germany. bmussil@dpz.eu.

ABSTRACT

Background: Bone marrow stromal cell antigen 2 (BST2), also known as tetherin, HM1.24 or CD317 represents a type 2 integral membrane protein, which has been described to restrict the production of some enveloped viruses by inhibiting the virus release from the cell surface. This innate antiviral mechanism is counteracted by the HIV-1 viral factor Vpu, targeting BST2 for cellular degradation. Since antiviral BST2 activity has been mainly confirmed by in vitro data, we investigated its role in vivo on the disease progression using the SIV/macaque model for AIDS. We determined BST2 expression in PBMC and leukocyte subsets of uninfected and SIV-infected rhesus macaques by real-time PCR and flow cytometry and correlated it with disease progression and viral load.

Results: Compared to pre-infection levels, we found increased BST2 expression in PBMC, purified CD4(+) lymphocytes and CD14(+) monocytes of SIV-infected animals, which correlated with viral load. Highest BST2 levels were found in progressors and lowest levels comparable to uninfected macaques were observed in long-term non-progressors (LTNPs). During acute viremia, BST2 mRNA increased in parallel with MX1, a prototype interferon-stimulated gene. This association was maintained during the whole disease course.

Conclusion: The detected relationship between BST2 expression and viral load as well as with MX1 indicate a common regulation by the interferon response and suggest rather limited influence of BST2 in vivo on the disease outcome.

No MeSH data available.


Related in: MedlinePlus

BST2 mRNA induction by type I interferon. a Fold induction of relative BST2 mRNA in PBMC from three uninfected rhesus macaques after stimulation with human Interferon Alpha A (Alpha 2a) for 16 h. Data are expressed as fold increase over baseline after normalization to pre-treatment values. Error bars represent standard deviation, b relative mRNA copies of BST2 in PBMC (shown in copy numbers per 100 copies of GAPDH) are illustrated in relation to plasma IFN-alpha levels from blood samples of 18 uninfected rhesus macaques 24 h after inoculation of replication incompetent adenovirus or fowl pox vectors. The black dashed line indicates the detection limit of the ELISA and c whole blood MX1 mRNA levels correlate with BST2 mRNA determined in 38 SIVmac251 infected rhesus macaques at 24 wpi. Relative mRNA levels are depicted as log-transformed copy numbers per 100 copies of GAPDH. Each data point represents one animal. Regression line is shown; r, Spearman’s correlation coefficient; p, p value
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Fig3: BST2 mRNA induction by type I interferon. a Fold induction of relative BST2 mRNA in PBMC from three uninfected rhesus macaques after stimulation with human Interferon Alpha A (Alpha 2a) for 16 h. Data are expressed as fold increase over baseline after normalization to pre-treatment values. Error bars represent standard deviation, b relative mRNA copies of BST2 in PBMC (shown in copy numbers per 100 copies of GAPDH) are illustrated in relation to plasma IFN-alpha levels from blood samples of 18 uninfected rhesus macaques 24 h after inoculation of replication incompetent adenovirus or fowl pox vectors. The black dashed line indicates the detection limit of the ELISA and c whole blood MX1 mRNA levels correlate with BST2 mRNA determined in 38 SIVmac251 infected rhesus macaques at 24 wpi. Relative mRNA levels are depicted as log-transformed copy numbers per 100 copies of GAPDH. Each data point represents one animal. Regression line is shown; r, Spearman’s correlation coefficient; p, p value

Mentions: Human BST2 expression can be influenced by type I interferons in vitro and in vivo [34–37]. Similarly, a dose-dependent increase in BST2 transcription by IFN-alpha in macaque PBMC in vitro was found (Fig. 3a). Furthermore, a direct correlation between BST2 transcription levels and in vivo plasma interferon-alpha levels exists (Fig. 3b). However, the application of the IFN-alpha assay is restricted due to its low sensitivity. Therefore, the influence of type I interferons on BST2 expression in vivo was assessed by quantifying the transcription levels of MX1, which has long been used as a reliable marker for type I interferon bioactivity, but may be influenced by other cytokines as well. We speculated that the increased levels of BST2 found in infected animals were associated with the interferon response known to be elevated in these animals [46, 47]. MX1 levels were assessed in a total of 38 monkeys at 24 wpi. Indeed, MX1 levels in whole blood correlated well with BST2 (Fig. 3c, p < 0.0001) indicating BST2 can be regulated by type I interferons in vivo.Fig. 3


Increased BST2 expression during simian immunodeficiency virus infection is not a determinant of disease progression in rhesus monkeys.

Mussil B, Javed A, Töpfer K, Sauermann U, Sopper S - Retrovirology (2015)

BST2 mRNA induction by type I interferon. a Fold induction of relative BST2 mRNA in PBMC from three uninfected rhesus macaques after stimulation with human Interferon Alpha A (Alpha 2a) for 16 h. Data are expressed as fold increase over baseline after normalization to pre-treatment values. Error bars represent standard deviation, b relative mRNA copies of BST2 in PBMC (shown in copy numbers per 100 copies of GAPDH) are illustrated in relation to plasma IFN-alpha levels from blood samples of 18 uninfected rhesus macaques 24 h after inoculation of replication incompetent adenovirus or fowl pox vectors. The black dashed line indicates the detection limit of the ELISA and c whole blood MX1 mRNA levels correlate with BST2 mRNA determined in 38 SIVmac251 infected rhesus macaques at 24 wpi. Relative mRNA levels are depicted as log-transformed copy numbers per 100 copies of GAPDH. Each data point represents one animal. Regression line is shown; r, Spearman’s correlation coefficient; p, p value
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4641394&req=5

Fig3: BST2 mRNA induction by type I interferon. a Fold induction of relative BST2 mRNA in PBMC from three uninfected rhesus macaques after stimulation with human Interferon Alpha A (Alpha 2a) for 16 h. Data are expressed as fold increase over baseline after normalization to pre-treatment values. Error bars represent standard deviation, b relative mRNA copies of BST2 in PBMC (shown in copy numbers per 100 copies of GAPDH) are illustrated in relation to plasma IFN-alpha levels from blood samples of 18 uninfected rhesus macaques 24 h after inoculation of replication incompetent adenovirus or fowl pox vectors. The black dashed line indicates the detection limit of the ELISA and c whole blood MX1 mRNA levels correlate with BST2 mRNA determined in 38 SIVmac251 infected rhesus macaques at 24 wpi. Relative mRNA levels are depicted as log-transformed copy numbers per 100 copies of GAPDH. Each data point represents one animal. Regression line is shown; r, Spearman’s correlation coefficient; p, p value
Mentions: Human BST2 expression can be influenced by type I interferons in vitro and in vivo [34–37]. Similarly, a dose-dependent increase in BST2 transcription by IFN-alpha in macaque PBMC in vitro was found (Fig. 3a). Furthermore, a direct correlation between BST2 transcription levels and in vivo plasma interferon-alpha levels exists (Fig. 3b). However, the application of the IFN-alpha assay is restricted due to its low sensitivity. Therefore, the influence of type I interferons on BST2 expression in vivo was assessed by quantifying the transcription levels of MX1, which has long been used as a reliable marker for type I interferon bioactivity, but may be influenced by other cytokines as well. We speculated that the increased levels of BST2 found in infected animals were associated with the interferon response known to be elevated in these animals [46, 47]. MX1 levels were assessed in a total of 38 monkeys at 24 wpi. Indeed, MX1 levels in whole blood correlated well with BST2 (Fig. 3c, p < 0.0001) indicating BST2 can be regulated by type I interferons in vivo.Fig. 3

Bottom Line: Highest BST2 levels were found in progressors and lowest levels comparable to uninfected macaques were observed in long-term non-progressors (LTNPs).During acute viremia, BST2 mRNA increased in parallel with MX1, a prototype interferon-stimulated gene.This association was maintained during the whole disease course.

View Article: PubMed Central - PubMed

Affiliation: Unit of Infection Models, German Primate Centre, Goettingen, Germany. bmussil@dpz.eu.

ABSTRACT

Background: Bone marrow stromal cell antigen 2 (BST2), also known as tetherin, HM1.24 or CD317 represents a type 2 integral membrane protein, which has been described to restrict the production of some enveloped viruses by inhibiting the virus release from the cell surface. This innate antiviral mechanism is counteracted by the HIV-1 viral factor Vpu, targeting BST2 for cellular degradation. Since antiviral BST2 activity has been mainly confirmed by in vitro data, we investigated its role in vivo on the disease progression using the SIV/macaque model for AIDS. We determined BST2 expression in PBMC and leukocyte subsets of uninfected and SIV-infected rhesus macaques by real-time PCR and flow cytometry and correlated it with disease progression and viral load.

Results: Compared to pre-infection levels, we found increased BST2 expression in PBMC, purified CD4(+) lymphocytes and CD14(+) monocytes of SIV-infected animals, which correlated with viral load. Highest BST2 levels were found in progressors and lowest levels comparable to uninfected macaques were observed in long-term non-progressors (LTNPs). During acute viremia, BST2 mRNA increased in parallel with MX1, a prototype interferon-stimulated gene. This association was maintained during the whole disease course.

Conclusion: The detected relationship between BST2 expression and viral load as well as with MX1 indicate a common regulation by the interferon response and suggest rather limited influence of BST2 in vivo on the disease outcome.

No MeSH data available.


Related in: MedlinePlus