Lara Manganaro

Friday, 26 October 2018 | 12:00 noon

Fondazione INGM, Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”, Milan, ITALY

IL-15 modulates HIV resistance through SAMHD1 inactivation in CD4+ T cells

(Host: M. Giacca)

HIV integrates into the host genome to create a persistent viralreservoir. Stimulation of CD4+ T lymphocytes with commonγc-chain cytokines renders these cells more susceptibleto HIV infection making them the key component of thereservoir itself. Among the different γc-chain cytokines, IL-15is specifically up-regulated during primary HIV/SIV infection,when the reservoir is established.

We observed that IL-15 stimulation relieves an early block toinfection by inducing the phosphorylation/inactivation ofthe restriction factor SAMHD1 in a JAK dependent manner.Our studies with high-resolution single cell immune profilingusing Mass Cytometry by time of Flight (CyTOF) revealedthat IL-15 stimulation altered the composition of CD4+ T cellpopulations by increasing proliferation of memory CD4+T cells, including CD4+ T stem memory cells (CD4+ TSCM).

IL-15 stimulated CD4+ TSCM, harboring phosphorylatedSAMHD1, were preferentially infected. We propose that IL-15 plays a pivotal role in creating a self-renewing, persistent HIV reservoir by facilitating infectionof CD4+ T cells with stem cell like properties. Time-limitedinterventions with JAK1 inhibitors, such as Ruxolitinib, shouldprevent the inactivation of the endogenous restriction factorSAMHD1 and protect this long-lived CD4+ T memory cellpopulation from HIV infection.