HIV-1 Env Heterogeneity: Cleavage, Trafficking, and Antigenic Consequences for Virions and Infected Cells

The HIV-1 Env glycoprotein mediates both cell-free and cell-to-cell viral transmission and represents the primary target for protective humoral immune responses. Studies examining antibody neutralization of cell-free and cell-to-cell HIV transmission have found that cell-to-cell transmission is more resistant to neutralization. This resistance may be explained in part by antigenically distinct Env populations on virions and infected cells. Cell-surface Env may be more heterogeneous due to variations in cleavage, glycosylation, and conformational state. Nevertheless, the mechanisms that maintain antigenically distinct Env populations at the cell surface and on virions remain unclear, despite virion assembly occurring at the plasma membrane. In this focused review, we consider how Env endocytosis and recycling influence Env incorporation into virions and antibody recognition. We further consider how Env cleavage may influence trafficking and endocytic fate. Given the central role of Env's cytoplasmic tail in engaging endosomal trafficking pathways, we review emerging structural models of the CT and discuss how its organization, symmetry, and conformational flexibility may contribute to Env trafficking and intracellular sorting. We also discuss how heterogeneous Env populations may influence antibody susceptibility. Finally, we review therapeutic strategies, including combinatorial antibodies and small-molecule Env modulators, that may enhance antibody recognition of infected cells and virions.