THE INTERLEUKIN 21 (IL 21)/ MICRORNA-29 (MIR-29) AXIS IS ASSOCIATED WITH NATURAL RESISTANCE TO HIV-1 INFECTION

BACKGROUND: Interleukin-21 (IL-21) modulates HIV-1 infection through the elicitation of different antiviral mechanisms, including Th17 lineage commitment and induction of microRNA (miR)-29, a miRNA endowed with anti-HIV activity. As miR-29 expression is significantly increased in HIV-1-exposed seronegative individuals (HESNs), we investigated the role of miR-29/IL21 axis in the natural control of HIV-1 infection. METHODS: Analyses were performed in two cohorts of sexually-exposed HESNs, one from Italy and another one from Colombia. Overall the two cohorts included 22 HESNs and 22 HIV-unexposed healthy controls (HCs) whose PBMCs were in vitro infected with an R5-tropic HIV-1Ba-L strain (Italian cohort) and an HIV-1-IIIB X4-tropic HIV-1 (Colombian cohort). Seven days post HIV-1 infection we evaluated: 1) p24 production (ELISA); 2) IL-21+/CD4+ and IL-17+/CD4+ T lymphocytes (FACS); 3) IL-17 concentration in supernatants (ELISA); and 4) IL-6, IL-17, and IL-21 mRNA and miR-29a, b, c expression by CD4+ T lymphocytes and PBMCs as well as perforin and granzymes in PBMCs (qPCR). The same analyses were performed on the 19 HIV-infected partners (HIV+). RESULTS: At baseline IL-6 expression alone was increased in HESNs compared to HCs. Thus, IL-21+/CD4+ and IL-17+/CD4+ T lymphocytes, as well as IL-21 and IL-17 expression and production were significantly augmented in HESNs compared to HCs. Interestingly, IL-21 upregulation correlated with a significantly increased expression of miR-29a, b, c in Italian cohort and with a reduced susceptibility to in vitro HIV-1 infection in HESNs alone. Differences in the expression of perforin and granzymes were observed in the Colombian cohort. CONCLUSIONS: The IL-21/miR-29 axis is upregulated by HIV-1 infection in HESNs suggesting its involvement in the natural resistance to HIV-1 infection in these individuals. Approaches that exogenously increase IL-21 production or prompt pre-existing cellular IL-21 reservoir could confine the magnitude of the initial HIV-1 infection.