HIV-1 envelope determinants for cell tropism and chemokine receptor use

Isolates of human immunodeficiency virus type-1 (HIV-1) display marked diff erences in their ability to replicate in macrophages and transformed T-cell lines in vitro, a property that has important implications for disease pat hogenesis. The restriction in replication between these two CD4-positive ce ll types is largely at the level of viral entry and is regulated by the vir al envelope (env) gene. The envelope protein (Env) is responsible for fusio n of the viral and host membranes, and a particular region of Env called th e V3-loop has been implicated in regulating viral tropism. However, other r egions of Env, such as the V1- and V2-loops, have been shown to modulate th e effects of the V3-loop. The discovery that Env initially binds the CD4 mo lecule on the target cell surface and then makes subsequent interactions wi th one of several members of the chemokine receptor family has greatly enha nced the molecular understanding of HIV-1 entry. The differential use of ch emokine receptors by different viral isolates and their expression in diffe rent cell types largely explains viral tropism. The same regions in Env res ponsible for virus tropism have also been shown to play an important role i n mediating chemokine receptor use. The recent crystallization of HIV-1 Env in complex with CD4 illuminates the architecture of the components involve d in mediating fusion between the viral and host membranes. The spatial rel ationship between variable structures of Env previously implicated in tropi sm and chemokine receptor use and conserved Env structures potentially invo lved in chemokine receptor binding are discussed.