Activation of the Wnt signaling pathway potently restricts HIV replication both in peripheral blood mononuclear cells (PBMCs) and astrocytes. Inducing Wnt signaling, leading to the activation of .beta.-catenin, for example, by the addition of lithium chloride (LiCl) inhibited the replication of a number of HIV isolates in PBMCs. Activating Wnt signaling, either with LiCl or other agents that target this pathway, is an approach to inhibit HIV replication.