Heterosexual transmission of HIV-1 across mucosal tissues involves a complex series of events that are not fully understood. It is clear however that glycosylation of the HIV envelope protein, which mediates entry into target cells, plays a critical and dynamic role in transmission. Sexual transmission is inefficient. A genetically diverse HIV-1 quasi-species replicating in the donor contracts through a genetic “bottleneck” such that often only a single transmitting virus (the founder) establishes infection in the recipient. The envelope proteins of transmitted viruses frequently encode a reduced number of N-linked glycosylation sites (PNGs). How reduced glycosylation increases transmission fitness is unknown. The aim of this study is to determine the impact of reduced PNGs on the biological and structural features of HIV env that might influence transmission fitness. Transmission linked glycans exert a pronounced influence on the interaction of the envelope with the CD4 and CCR5 receptors, and with Integrin a4b7. Recently a second transmission signature, a basic residue at position #12 in the gp120 leader peptide has also been identified. We find that this signature impacts qualitative aspects of env glycosylation and its interaction with CD4, CCR5 and DC-SIGN. In summary, the two known signatures of founder envs, both impact env glycosylation, which in turn impacts env structure and its interaction with cell-surface receptors critical to mucosal transmission. These observations may provide insights into the design of improved HIV immunogens for vaccine development.
© 2013 Lippincott Williams & Wilkins, Inc.