sphingosine-1-phosphate and HIV-Infections

Topics: CD4-Positive T-Lymphocytes; HIV Infections; HIV-1; Humans; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); SAM Domain and HD Domain-Containing Protein 1; Sphingosine; Virus Latency

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.

Topics: Fingolimod Hydrochloride; HIV Infections; HIV-1; Humans; Lysophospholipids; Phosphorylation; SAM Domain and HD Domain-Containing Protein 1; Signal Transduction; Sphingosine; Sphingosine 1 Phosphate Receptor Modulators; T-Lymphocytes; Virus Latency; Virus Replication

The determinants of HIV-1-associated lymphadenopathy are poorly understood. We hypothesized that lymphocytes could be sequestered in the HIV-1+ lymph node (LN) through impairments in sphingosine-1-phosphate (S1P) responsiveness. To test this hypothesis, we developed novel assays for S1P-induced Akt phosphorylation and actin polymerization. In the HIV-1+ LN, naïve CD4 T cells and central memory CD4 and CD8 T cells had impaired Akt phosphorylation in response to S1P, whereas actin polymerization responses to S1P were impaired dramatically in all LN maturation subsets. These defects were improved with antiretroviral therapy. LN T cells expressing CD69 were unable to respond to S1P in either assay, yet impaired S1P responses were also seen in HIV-1+ LN T cells lacking CD69 expression. Microbial elements, HIV-1, and interferon α - putative drivers of HIV-1 associated immune activation all tended to increase CD69 expression and reduce T-cell responses to S1P in vitro. Impairment in T-cell egress from lymph nodes through decreased S1P responsiveness may contribute to HIV-1-associated LN enlargement and to immune dysregulation in a key organ of immune homeostasis.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Retroviral Agents; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Cell Line, Tumor; Cells, Cultured; Female; Flow Cytometry; Gene Expression; HIV Infections; HIV-1; Humans; Lectins, C-Type; Lymph; Lymphocyte Activation; Lysophospholipids; Male; Middle Aged; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Lysosphingolipid; Reverse Transcriptase Polymerase Chain Reaction; Sphingosine; Sphingosine-1-Phosphate Receptors; T-Lymphocytes