Fingolimod increases cellular resistance to HIV-1 infection and limits viral reservoir size in peripheral CD4+...

Fingolimod, a treatment for multiple sclerosis (MS), decreases autoreactive lymphocytes by lymph node sequestration. In vitro, fingolimod decreases HIV-1 infection and viral reservoir (VR) through SAMHD1 phosphorylation inhibition and reducing lymphocyte activation and CD4 expression. We identified an exceptional MS patient infected with HIV-1 (HIV+ MS+) while on fingolimod therapy and we have analyzed its impact on HIV-1 infection in vivo and ex vivo.

The case was the HIV+ MS+ patient. Controls were 20 PWH (HIV+ MS-), five HIV-negative donors (HIV-MS) and three HIV-negative MS patients treated with fingolimod (HIV-MS+), as the case reported. VR was quantified by IPDA and HIV-1 intracellular RNAs (icRNAs) by ddPCR in peripheral blood CD4+ T-cells. CD4+ T-cells were infected in vitro with an NL4.3-Renilla strain. Immunophenotype, activation markers and phosphorylated SAMHD1 levels were determined by flow cytometry.

At diagnosis, HIV+ MS+ viral load was nine-fold lower than HIV+ MS- treated at similar Fiebig stage. One year after ART, HIV+ MS+ showed lower intact and defective VR than the HIV+ MS- control group (28-and six-fold decrease respectively). After three years on ART no intact proviruses were detected in HIV+ MS+ . HIV-1 in vitro infection was decreased in HIV+ MS+ and HIV- MS + vs HIV+ MS- and HIV-MS-. CD4+ T-cells levels from fingolimod treated patients were lower and showed decreased CD4 expression, lymphocyte activation and SAMHD1 phosphorylation vs HIV- MS-. icRNAs were significantly increased after T-cell activation in the HIV+ MS-, while they were barely detected at resting and activated HIV+ MS+ CD4+ T-cells.

We describe a strong restriction to HIV-1 infection and replication in vivo and ex vivo leading to indetectable intact VR in HIV+ MS+ after three years of ART. Potential mechanisms of restriction are CD4 downregulation, T-cell activation inhibition, and SAMHD1 activity enhancement.