P39.06
Background: The design of effective vaccines and microbicides requires understanding early steps in mucosal transmission. As the genetic bottleneck at transmission favors variants with fewer potential N-glycosylation sites (PNGs) and shorter variable loops, we investigated whether Envelope (Env) PNGs could influence the ability of variants to cross the genital mucosa by altering gp120 interactions with DC-SIGN, which could favour transfer to CD4+ cells, and also alter localized immune responses in the genital epithelium.
Methods: We initially determined whether pseudovirus-Envs from transmitted founders (TF) had enhanced DC-SIGN binding, trans-infection and increased IL-10 secretion over matched chronic Envs. As DC-SIGN interactions with Env favors high mannose N-glycans, we also deleted gp120 PNGs bearing high mannose glycans either singly, or in combination, in matched CAP239 Env T/F and chronic clones.
Results: T/F Envs induced more IL-10 secretion than chronic controls. When PNGs were deleted from the CAP239 envs, the effect on pseudovirion entry, DC-SIGN binding and trans-infection was clone specific, suggesting that specific N-glycans affect Env function differently in different clones. For example deletion of PNG 448 reduced entry efficiency, DC-SIGN binding and trans-infection of TF by ∼50% when compared to wild type, while either enhancing or maintaining these phenotypes in the chronic infection clone. Only deletion of the PNG 241 reduced IL-10 induction for T/F clones.
Conclusions: As pseudovirion entry efficiencies of most PNG mutants were reduced for both CAP239 Env clones, it is difficult to determine the role that each might play in DC-SIGN interactions. However, the TF Envs induced MDDCs to secrete higher levels of IL-10 compared to matched chronic infection controls, suggesting that localized anti-inflammatory responses in the genital epithelium might play a role in HIV transmission.
