Vpr Mediates Immune Evasion and HIV-1 Spread.

Abstract

The molecular mechanisms by which human immunodeficiency virus (HIV-1) evades immunity to cause persistent infection remain incompletely characterized. Viral protein R (Vpr) is conserved in all primate lentiviruses, including HIV-1. Previous studies have demonstrated that Vpr is required for maximal infection of T lymphocytes in vivo. However, Vpr does not enhance HIV-1 infection of T lymphocytes under standard in vitro infection conditions, and the mechanism of Vpr function is poorly understood. Our work demonstrates that Vpr prevents the induction of a type I interferon-stimulated antiviral response in macrophages that targets Env and Env-containing virions for lysosomal degradation. By preventing this response, Vpr promotes Env-dependent virological synapse formation and enables efficient spread of HIV-1 from macrophages to activated T lymphocytes. This mode of spread requires direct cell-to-cell contact and is highly resistant to neutralizing antibodies. These studies provide a mechanistic explanation for the evolutionary conservation and function of Vpr.