Cytokines are a family of proteins that play important roles in immune cell communication. The best-known example is interleukin-2 (IL-2), which is FDA-approved as a therapy for kidney cancer. Many cytokines have been evaluated in HIV infection and one of the latest candidates being considered for human testing is IL-21. Laboratory and animal model research indicates IL-21 can enhance natural killer cell and CD8 T cell activity, and clinical trials are already underway in people with cancers.
At several recent conferences, including the IAS Towards an HIV Cure Symposium in 2014, Mirko Paiardini has presented results from a study of IL-21 in SIV-infected macaques suggesting the cytokine may ameliorate immune activation and limit the size of the latent viral reservoir (see most recently the webcast of a talk by Luca Micci from Paiardini’s laboratory at CROI 2015). A newly published open access paper in Nature Communications describes an additional, novel mechanism of action against HIV: the researchers found that IL-21 enhances antiviral activity in CD4 T cells by inducing expression of microRNA-29. MicroRNAs are short sequences of RNA that do not encode proteins but can act to regulate cellular gene expression, and microRNA-29 has previously been reported to inhibit HIV replication in vitro. When administered to humanized mice challenged with HIV, IL-21 significantly lowered HIV replication levels.
The new results further bolster the rationale for investigating recombinant IL-21 in the setting of HIV infection (preliminary evidence that IL-21 might have beneficial effects has been covered on the blog previously; see Interleukin-21 in Chronic Viral Infection and IL-21 in HIV Infection). Published findings from trials in cancer state that IL-21 is “generally well tolerated” but note a range of side effects, albeit considerably milder than those seen with IL-2. It's yet not clear if dosing in HIV would need to be similar to that studied in cancer.
Nature Communications 6, Article number: 7562 doi:10.1038/ncomms8562
Stanley Adoro, Juan R. Cubillos-Ruiz, Xi Chen, Maud Deruaz, Vladimir D. Vrbanac, Minkyung Song, Suna Park, Thomas T. Murooka, Timothy E. Dudek, Andrew D. Luster, Andrew M. Tager, Hendrik Streeck, Brittany Bowman, Bruce D. Walker, Douglas S. Kwon, Vanja Lazarevic & Laurie H. Glimcher
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.