Fingolimod inhibits multiple stages of the HIV-1 life cycle

Author summary Human Immunodeficiency Virus (HIV) is currently managed by antiretroviral drugs, which may have side effects and are of limited use in prevention of transmission of the virus between individuals. We investigated an alternative tactic to combat HIV infection by harnessing a component of the immune system involved in the progression of infection, Sphingosine-1-phosphate (S1P). We tested a drug known to modulate the action of S1P receptors, FTY720 (Fingolimod) in human immune cells to investigate whether targeting S1P could inhibit HIV infection. We observed that FTY720 was able to block infection in human CD4 T cells by hindering multiple steps in the life cycle of HIV. FTY720 is already clinically approved and did not affect the viability of the human cells in our model system; therefore, we believe that this compound may be a promising novel therapy for HIV treatment and prevention. Antiretroviral drugs that target various stages of the Human Immunodeficiency Virus (HIV) life cycle have been effective in curbing the AIDS epidemic. However, drug resistance, off-target effects of antiretroviral therapy (ART), and varying efficacy in prevention underscore the need to develop novel and alternative therapeutics. In this study, we investigated whether targeting the signaling molecule Sphingosine-1-phosphate (S1P) would inhibit HIV-1 infection and generation of the latent reservoir in primary CD4 T cells. We show that FTY720 (Fingolimod), an FDA-approved functional antagonist of S1P receptors, blocks cell-free and cell-to-cell transmission of HIV and consequently reduces detectable latent virus. Mechanistically, FTY720 impacts the HIV-1 life cycle at two levels. Firstly, FTY720 reduces the surface density of CD4, thereby inhibiting viral binding and fusion. Secondly, FTY720 decreases the phosphorylation of the innate HIV restriction factor SAMHD1 which is associated with reduced levels of total and integrated HIV, while reducing the expression of Cyclin D3. In conclusion, targeting the S1P pathway with FTY720 could be a novel strategy to inhibit HIV replication and reduce the seeding of the latent reservoir.