Prior to our work, others had observed the potential of an S1P receptor agonist to reactivate HIV from latency as well as a decreased response to S1P signaling in chronically infected individuals [14, 31, 32]; however, the role of S1P signaling in establishment of infection and the potential to modulate this pathway to alter the course of infection or prevent establishment of the latent reservoir in CD4 T cells had not been reported. Here, CD4 is linked to infection.