An investigation into the use of fingolimod as antiretroviral therapy against HIV-1 revealed 2 potential targets for the immunosuppressive drug: S1P receptors and SAMHD1, an antiviral restriction factor.
An investigation into the use of fingolimod (FTY720; Gilenya, Novartis) as antiretroviral therapy (ART) against HIV-1 revealed 2 potential targets for the immunosuppressive drug that has long been a mainstay for patients in the midst of multiple sclerosis flare-ups, report study results in PLoS Pathogens: sphingosine-1-phosphate (S1P) receptors and SAM domain and HD domain-containing protein 1 (SAMHD1), an antiviral restriction factor.
The 2 targets have to do with blocking active HIV infection and reducing latent reservoirs of the virus. FTY720 was chosen because it’s a known modulator of S1P receptors and is well tolerated as a daily oral medication.
"While antiretroviral drugs have been effective in treating HIV thus far, drug resistance, negative side effects of antiretroviral therapy, and its varying efficacy underscore the need to develop alternative treatment and prevention options," said Alberto Bosque, PhD, MBA, of the George Washington University School of Medicine and Health Sciences and one of the study’s authors, in a statement.
Bosque and his team recognized the need for ARTs that “specifically target latent infection,” which can be reactivated at any time, they noted, and their results show that not only did fingolimod prevent HIV-1 from binding to S1P receptors and block infection, but it also activated SAMHD1, which breaks down the deoxynucleoside triphosphates HIV needs to replicate.
To block infection by and prevent binding of HIV, FTY720 helped to reduce the surface density of CD4 T cells, decreased the phosphorylation of SAMHD1, and reduced expression of cyclin D3. The investigators first isolated naïve CD4 T cells from peripheral blood mononuclear cells in test tubes before activating them with αCD3/28, treating them with FTY720 on day 5, and infecting them with X4- or R5-tropic HIV-1 (NL4-3 or NL-AD8, respectively) on day 7.
Results show that the higher the pretreatment dose of FTY720, the greater the mean (SD) reduction of frequency of infected cells for NL4-3:
Similar results were seen for reduction of frequency of infected cells for NL-AD8:
To see how FTY720 affects cell-to-cell transmission of HIV, the authors cultured CD4 T cells in 96-well round bottom plates for 3 days. “We observed a marked decrease in productive infection with 66 nM FTY720,” they noted, for a mean reduction in p24 of 54.4% (16.02%). Results were similar whether the CD4 T cells were infected with X4- or R5-tropic virus.
In addition, to establish how FTY720 affects viral latency, the investigators treated HIV-infected cells with 66 nM FTY720 on days 10 through 13, then removed it from the culture before culturing the cells with 1 mcM raltegravir and 0.5 mcM nelfinavir from days 13 through 17. On day 17, they saw mean reductions in both the total and integrated HIV DNA of 51.45% (3.19%) and 60.41% (19.59%), respectively.
“This result indicates that FTY720 inhibits infection at or prior to reverse transcription,” the authors noted.
Lastly, to measure FTY720’s effect on SAMHD1, central memory T cells were treated on day 10 with 100 nM FTY720 for 24 hours. There was a significant mean (SD) reduction in phosphorylated SAMHD1 of 36.63% (4.47%), but not overall SAMHD1 levels, which indicated its active form increased. But the investigators say this finding needs further investigation.
“Our results indicate that FTY720 may be an exciting novel therapy for HIV infection,” the authors concluded. “FTY720 is already clinically approved and well-tolerated and we show that it also restricts HIV infection of CD4 T cells.”
Resop RS, Fromentin R, Newman D, et al. Fingolimod inhibits multiple stages of the HIV-1 life cycle. PLoS Pathog. Published online August 13, 2020. doi:10.1371/journal.ppat.1008679