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IL-21 induces antiviral microRNA-29 in CD4 T cells to limit HIV-1 infection.

Adoro S, Cubillos-Ruiz JR, Chen X, Deruaz M, Vrbanac VD, Song M, Park S, Murooka TT, Dudek TE, Luster AD, Tager AM, Streeck H, Bowman B, Walker BD, Kwon DS, Lazarevic V, Glimcher LH - Nat Commun (2015)

Bottom Line: Here we take advantage of tractable primary human lymphoid organ aggregate cultures to show that IL-21 directly suppresses HIV-1 replication, and identify microRNA-29 (miR-29) as an antiviral factor induced by IL-21 in CD4 T cells.IL-21 promotes transcription of all miR-29 species through STAT3, whose binding to putative regulatory regions within the MIR29 gene is enriched by IL-21 signalling.Notably, exogenous IL-21 limits early HIV-1 infection in humanized mice, and lower viremia in vivo is associated with higher miR-29 expression.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Medicine, Weill Cornell Medical College, Cornell University, 1300 York Avenue, New York, New York 10065, USA [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.

ABSTRACT
Initial events after exposure determine HIV-1 disease progression, underscoring a critical need to understand host mechanisms that interfere with initial viral replication. Although associated with chronic HIV-1 control, it is not known whether interleukin-21 (IL-21) contributes to early HIV-1 immunity. Here we take advantage of tractable primary human lymphoid organ aggregate cultures to show that IL-21 directly suppresses HIV-1 replication, and identify microRNA-29 (miR-29) as an antiviral factor induced by IL-21 in CD4 T cells. IL-21 promotes transcription of all miR-29 species through STAT3, whose binding to putative regulatory regions within the MIR29 gene is enriched by IL-21 signalling. Notably, exogenous IL-21 limits early HIV-1 infection in humanized mice, and lower viremia in vivo is associated with higher miR-29 expression. Together, these findings reveal a novel antiviral IL-21-miR-29 axis that promotes CD4 T-cell-intrinsic resistance to HIV-1 infection, and suggest a role for IL-21 in initial HIV-1 control in vivo.

No MeSH data available.


Related in: MedlinePlus

Relationship between miR-29 expression and HIV-1 disease in humans.(a) Expression of miR-29b in HIV-negative (Neg, n=10), HIV-1-infected untreated progressors (Prog, n=19) and elite controllers (EC, n=10). Data are compared with the unpaired Student's t-test. (b) Correlation between miR-29b and plasma HIV-1 titer in untreated HIV-1-infected progressors. Each data point represents an individual and Spearman's correlation coefficient (r) and P values are shown.
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f5: Relationship between miR-29 expression and HIV-1 disease in humans.(a) Expression of miR-29b in HIV-negative (Neg, n=10), HIV-1-infected untreated progressors (Prog, n=19) and elite controllers (EC, n=10). Data are compared with the unpaired Student's t-test. (b) Correlation between miR-29b and plasma HIV-1 titer in untreated HIV-1-infected progressors. Each data point represents an individual and Spearman's correlation coefficient (r) and P values are shown.

Mentions: Our preceding results strongly supported a significant contribution of an IL-21–miR-29 axis in HIV-1 control prompting us to next determine the relationship between miR-29 and HIV-1 infection in human subjects. We quantified miR-29 expression in peripheral blood CD4 T cells from uninfected, treatment naïve HIV-infected progressors (Prog) and EC who suppress HIV in the absence of antiretroviral drugs32. Similar to CD4 T cells from HIV-1-infected HLACs (Fig. 4a), we detected marked downregulation of miR-29b expression in CD4 T cells from untreated HIV-infected Progs compared with uninfected and ECs subjects (Fig. 5a). Notably, among untreated HIV-infected Progs, miR-29b expression inversely correlated (Spearman correlation coefficient (r)=−0.5080; P=0.0314) with plasma HIV titres (Fig. 5b). Together, these results from human subjects are consistent with a protective role for miR-29 in HIV-1 control and suggest that downregulated miR-29 expression could represent a signature of progressive HIV-1 disease.


IL-21 induces antiviral microRNA-29 in CD4 T cells to limit HIV-1 infection.

Adoro S, Cubillos-Ruiz JR, Chen X, Deruaz M, Vrbanac VD, Song M, Park S, Murooka TT, Dudek TE, Luster AD, Tager AM, Streeck H, Bowman B, Walker BD, Kwon DS, Lazarevic V, Glimcher LH - Nat Commun (2015)

Relationship between miR-29 expression and HIV-1 disease in humans.(a) Expression of miR-29b in HIV-negative (Neg, n=10), HIV-1-infected untreated progressors (Prog, n=19) and elite controllers (EC, n=10). Data are compared with the unpaired Student's t-test. (b) Correlation between miR-29b and plasma HIV-1 titer in untreated HIV-1-infected progressors. Each data point represents an individual and Spearman's correlation coefficient (r) and P values are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4481879&req=5

f5: Relationship between miR-29 expression and HIV-1 disease in humans.(a) Expression of miR-29b in HIV-negative (Neg, n=10), HIV-1-infected untreated progressors (Prog, n=19) and elite controllers (EC, n=10). Data are compared with the unpaired Student's t-test. (b) Correlation between miR-29b and plasma HIV-1 titer in untreated HIV-1-infected progressors. Each data point represents an individual and Spearman's correlation coefficient (r) and P values are shown.
Mentions: Our preceding results strongly supported a significant contribution of an IL-21–miR-29 axis in HIV-1 control prompting us to next determine the relationship between miR-29 and HIV-1 infection in human subjects. We quantified miR-29 expression in peripheral blood CD4 T cells from uninfected, treatment naïve HIV-infected progressors (Prog) and EC who suppress HIV in the absence of antiretroviral drugs32. Similar to CD4 T cells from HIV-1-infected HLACs (Fig. 4a), we detected marked downregulation of miR-29b expression in CD4 T cells from untreated HIV-infected Progs compared with uninfected and ECs subjects (Fig. 5a). Notably, among untreated HIV-infected Progs, miR-29b expression inversely correlated (Spearman correlation coefficient (r)=−0.5080; P=0.0314) with plasma HIV titres (Fig. 5b). Together, these results from human subjects are consistent with a protective role for miR-29 in HIV-1 control and suggest that downregulated miR-29 expression could represent a signature of progressive HIV-1 disease.

Bottom Line: Here we take advantage of tractable primary human lymphoid organ aggregate cultures to show that IL-21 directly suppresses HIV-1 replication, and identify microRNA-29 (miR-29) as an antiviral factor induced by IL-21 in CD4 T cells.IL-21 promotes transcription of all miR-29 species through STAT3, whose binding to putative regulatory regions within the MIR29 gene is enriched by IL-21 signalling.Notably, exogenous IL-21 limits early HIV-1 infection in humanized mice, and lower viremia in vivo is associated with higher miR-29 expression.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Medicine, Weill Cornell Medical College, Cornell University, 1300 York Avenue, New York, New York 10065, USA [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.

ABSTRACT
Initial events after exposure determine HIV-1 disease progression, underscoring a critical need to understand host mechanisms that interfere with initial viral replication. Although associated with chronic HIV-1 control, it is not known whether interleukin-21 (IL-21) contributes to early HIV-1 immunity. Here we take advantage of tractable primary human lymphoid organ aggregate cultures to show that IL-21 directly suppresses HIV-1 replication, and identify microRNA-29 (miR-29) as an antiviral factor induced by IL-21 in CD4 T cells. IL-21 promotes transcription of all miR-29 species through STAT3, whose binding to putative regulatory regions within the MIR29 gene is enriched by IL-21 signalling. Notably, exogenous IL-21 limits early HIV-1 infection in humanized mice, and lower viremia in vivo is associated with higher miR-29 expression. Together, these findings reveal a novel antiviral IL-21-miR-29 axis that promotes CD4 T-cell-intrinsic resistance to HIV-1 infection, and suggest a role for IL-21 in initial HIV-1 control in vivo.

No MeSH data available.


Related in: MedlinePlus