Abstract
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.
Highlights
Human Immunodeficiency Virus (HIV-1) remains a global health burden, with nearly 40 million people currently living with HIV
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
Summary
Human Immunodeficiency Virus (HIV-1) remains a global health burden, with nearly 40 million people currently living with HIV. Treatment of infection is lifelong, due to the ability of the virus to establish latency by integrating its genome into that of host cells, which become quiescent and long-lived, resulting in the potential of viral reactivation at a future time [1,2,3,4,5,6,7,8]. Available antiretroviral therapies (ART) are able to control viral load but do not target latent infection and have off-target effects in many individuals [11]. For this reason, discovery of novel methods to target establishment of HIV infection and latency is crucial
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