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

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.

MicroRNA and HIV

“…It has been observed that HIV infection causes changes in the profile of some miRNA such as miR-29a, miR-29b, miR-125b, miR-223, miR-382, miR-198, etc. This changes have been observed in infected CD4 + T cell, PBMCs or serum [1][2][3]6,[8][9][10][19][20][21]. However, it should be taken into account that miRNAs may be regulated in different ways providing different profiles depending on the different immune compartments.…”

“…For example, miR-150 in HIV infected patients is much higher in plasma than in the cell compartments [1]. Cellular miRNA play a critical role in the pathogenesis of HIV intervening in viral infection, latency and mediating cell intrinsic resistance [6,10,19]. Here, we will focus on the role of miRNAs as innate antiretroviral defense.…”

“…In plants, invertebrates and mammals it has been described that miRNAs play a crucial role in innate antiretroviral defense [10]. There are few described miRNAs having a direct effect on the virus but large numbers of them affect HIV indirectly throughout the regulation of factors that are necessary for viral cycle [1,2,6,[8][9][10]19,21].…”

“…miR-29 can bind directly to 3' UTR of viral mRNA, inhibiting virus protein translation and virus replication [4,9,10,19]. miR-149 joins to vpr gene, which is involved in the transport of proviral DNA to the nucleous [4].…”

“…It has been described different miRNAs profiles in HIV elite controllers (miR-9, miR-29, miR-31, miR-34a, miR-125b, miR-150, miR-155, etc), suggesting that miRNAs could contribute to a slower progression to AIDS [1][2][3]5,8,10,19]. For instance, a study analyzed 175 circulating miRNAs in plasma of three groups of individuals: elite controllers, chronic progressors and healthy donors.…”