HIV-1 Reprograms CD4 T Cell Responses by Impairing Antigen-specific Communication with Dendritic Cells

HIV-1 infection causes general dysfunction of adaptive immune cells that persists even under therapy but the underlying mechanisms remain elusive. Antigen-specific interactions of the main target cells of HIV, CD4 T cells, with dendritic cells (DCs) orchestrate global T cell responses and convey help to CD8 T cells. Here we report that HIV-1, by virtue of its pathogenesis factor Nef, impairs activation and transcriptionally reprograms CD4 T cells to dampen Th1 differentiation in response to antigen-specific stimulation by DCs. These alterations also disrupt functional communication to DCs to reduce DC activation and limit Th1 helper cytokine production. Mechanistically, Nef achieves this modulation of antigen-specific CD4 T cell function by reducing T cell surface levels of CD4. These results define modulation of CD4 T cell-DC communication as pathogenic principle by which HIV-1 disrupts adaptive immunity and emphasize the direct role of CD4 in immune cell communication. One Sentence Summary HIV-1 suppresses Th1 polarization by disrupting the communication between CD4 T cells and Dendritic cells through cell surface CD4 downregulation by the viral pathogenesis factor Nef.