The Vpu Protein and its Role in HIV-1 Pathogenesis

The Vpu protein of human immunodeficiency virus type 1 (HIV-1) is a small transmembrane protein that is synthesized late in the virus life cycle. Several functions have been ascribed to the Vpu protein in the life cycle of HIV-1. First, Vpu has been shown to interact with the CD4 molecule in the rough endoplasmic reticulum (RER), the receptor for HIV-1 entry, and this interaction is thought to result in re-translocation across the RER and subsequent degradation via the proteasome pathway. Secondly, Vpu has been shown to enhance virion release from infected cells by some unknown mechanism. While much has been learned about the function of Vpu in cell culture systems, its exact role in HIV-1 pathogenesis (HIV-1 only causes disease in humans and chimpanzees) is still unknown. This has been primarily due to the lack of a suitable primate model system since vpu is found only in HIV-1 and simian immunodeficiency virus isolated from chimpanzees (SIVcpz). With the recent development of the pathogenic simian-human immunodeficiency virus (SHIV) / macaque model, in which the tat, rev, vpu and env genes of HIV-1 are expressed in the genetic background of SIV, it will now be possible to assess the role of the vpu gene product in a relevant animal model. This review will focus on the current understanding of the structure-function relationships of Vpu protein and the use of the SHIV model to assess the role of Vpu in HIV-1 pathogenesis.