The tale of the long tail: the cytoplasmic domain of HIV-1 gp41.

Envelope glycoproteins (Env) of lentiviruses typically possess unusually long cytoplasmic domains, often 150 amino acids or longer. It is becoming increasingly clear that these sequences contribute a diverse array of functional activities to the life cycle of their viruses. The cytoplasmic domain of gp41 (gp41CD) is required for replication of human immunodeficiency virus type 1 (HIV-1) in most but not all cell types, whereas it is largely dispensable for replication of simian immunodeficiency virus (SIV). Functionally, gp41CD has been shown to regulate rapid clathrin-mediated endocytosis of Env. The resultant low levels of Env expression at the cell surface likely serve as an immune avoidance mechanism to limit accessibility to the humoral immune response. Intracellular trafficking of Env is also regulated by gp41CD through interactions with a variety of cellular proteins. Furthermore, gp41CD has been implicated in the incorporation of Env into virions through an interaction with the virally encoded matrix protein. Most recently, the gp41CDs of HIV-1 and SIV were shown to activate the key cellular-transcription factor NF-κB via the serine/threonine kinase TAK1. Less well understood are the cytotoxicity- and apoptosis-inducing activities of gp41CD as well as potential roles in modulating the actin cytoskeleton and overcoming host cell restrictions. In this review, we summarize what is currently known about the cytoplasmic domains of HIV-1 and SIV and attempt to integrate the wealth of information in terms of defined functional activities.