Background
Fingolimod, immunomodulating drug indicated for people with multiple sclerosis (MS), is a sphingosine-1-phosphate-receptor modulator that reduces CD4+Tcells levels by lymph node sequestration. In vitro, fingolimod decreases HIV infection and viral reservoir (VR) by inhibiting SAMHD1 phosphorylation, lymphocyte activation and reducing CD4 expression. We identified a MS patient who acquired HIV (HIV+MS+) during fingolimod treatment and we analysed its impact on HIV infection in vivo and ex vivo.
Methods
We included 4 MS patients treated with fingolimod: 1 HIV+MS+ (Fiebig V) and 3 HIV-MS+. As controls we analysed 20 people with HIV treated at FiebigV-VI (HIV+MS-) and 5 healthy donors (HD). VR was quantified by IPDA. 5’elongated (LLTR), unspliced (Pol), polyadenylated (PolyA) and multiply spliced (TatRev) HIV intracellular RNA (icRNA) was quantified by ddPCR in resting and activated CD4+Tcells. In vitro CD4+Tcells were infected with a Renilla-reporter HIV. NK and CD4+Tcells, activation and phosphorylated SAMHD1 levels were determined by flow cytometry.
Results
At diagnosis, viral load in HIV+MS+ patient was lower than the HIV+MS- at Fiebig V-VI (38498 vs 331500 cp/mL). One year after ART, HIV+MS+ showed a lower intact and defective VR than the PWH control group (19 vs 535; 88 vs 539 cp/106CD4+Tcells respectively). Notably, after 3 years on ART in HIV+MS+ patient, intact VR was undetectable (0 cp/10⁶CD4+Tcells), while defective VR remained low. LLTR, Pol, PolyA and TatRev significantly increased after CD4+Tcells activation on the HIV+MS- group (7.5, 38.7, 74.8 and 1151.7-folds respectively), while they were lowly detected before and after activation in the HIV+MS+(1.3, 1, 0.2 and 3.8-folds respectively). CD4+T-cells from MS patients showed decreased CD4 expression, lymphocyte activation and SAMHD1 phosphorylation. HIV replication was strongly decreased (>95%) in purified CD4+Tcells from HIV+MS+ and HIV-MS+ after in vitro infection in comparison to HIV+MS- and HD. NK-memory-like cell levels from HIV+MS+ were higher compared with HIV+MS-, HIV-MS+ or HD (43% vs 24%, 1.6% and 2.3% respectively).
Conclusions
We report the first case of MS patient who acquired HIV during fingolimod treatment. Fingolimod restricts HIV infection and replication in vivo and ex vivo leading to long-lasting VR reduction, particularly in intact proviruses. Potential mechanisms of fingolimod induced restriction are downregulation of CD4, block of CD4+Tcell activation and increased SAMHD1 activity.