July 15, 2015
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.
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.
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