Dissemination of HIV-1 from latently infected cells to resting CD4+ T cells requires CD4 and actin remodeling.

Abstract

Abstract The major barrier to HIV-1 eradication is the replication-competent proviruses in long-lived latently infected CD4+ T cells. Current efforts to purge latently HIV-1-infected cells have focused on developing “shock and kill” approaches to force reactivation of the proviruses in these cells to be killed after reactivation of virus gene expression by viral cytopathic effects, host immune responses, or both. Cell-free virus infection and cell-to-cell transmission via the virological synapses (VS) are the two modes of HIV-1 dissemination between CD4+ T cells. Several studies have demonstrated that cell-to-cell spread, in which HIV-1 disseminates through direct contact of infected cells with surrounding uninfected cells, is a far more efficient process than that of cell-free virus infection. In this work, we studied the mechanism of cell-to-cell transmission between primary CD4+ T cells and the HIV-1 latently infected cell line ACH-2. When primary resting CD4+ T cells were co-cultured with ACH-2 cells under latency reversing agent Romidepsin stimulation, about 20.7% cells had been infected without becoming activated. Additionally, blocking with anti-CD4 or anti-gp120 neutralizing antibodies (VRC01) decreased de novo infection, and neither anti-CXCR4 antibodies nor chemokine inhibitors demonstrated the ability to inhibit cell-to-cell transmission. We also found that co-cultured resting CD4+ T cells carried higher levels of active cofilin, the actin-depolymerizing factor, suggesting actin plays a role in VS formation and viral pathogenesis. These results suggest HIV-1 Env gp120 binds with the CD4 receptor, not chemokine coreceptor to form VS during cell-to-cell transmission.