As SPHK inhibition, in addition to S1PR modulation with FTY720, hinders HIV-1 cell-to-cell transmission, our results suggest that SPHK1 and SPHK2 are involved in HIV-1 infection of primary CD4 T cells and represent unique targets toward halting HIV-1 infection. The gene discussed is SPHK1; the disease is HIV-1 infection.