Griffithsin retains anti-HIV-1 potency with changes in gp120 glycosylation and complements broadly neutralizing antibodies PGT121 and PGT126.

Fischer, Kathryn; Nguyen, Kimberly; LiWang, Patricia J

Griffithsin (Grft) is an antiviral lectin that has been shown to potently inhibit HIV-1 by binding high mannose N-linked glycosylation sites on HIV-1 gp120. A key factor for Grft potency is glycosylation at N295 of gp120, which is directly adjacent to N332, a target glycan for an entire class of broadly neutralizing antibodies (bNAbs). Here we unify previous work on the importance of other glycans to Grft potency against HIV-1, and Grft's role in mediating conformational change of gp120, by mutating nearly every glycosylation site in gp120. In addition to significant loss of Grft activity by removal of glycosylation at N295, glycan absence at N332 or N448 was found to have moderate effects on Grft potency. Interestingly, in the absence of N295, Grft effectiveness could be improved by mutation that results in the glycan at N448 shifting to N446, indicating that glycan importance may be related to their effect on glycosylation density. Grft's ability to alter the structure of gp120, exposing the CD4 binding site, only correlated with the presence of glycosylation at N295 in B clade strains, but not C clade strains. We further demonstrate that Grft can rescue the activity of bNAbs PGT121 and PGT126 in the event of loss or shift of glycosylation at N332, where the bNAbs suffer a drastic loss of potency. Despite targeting the same region, Grft in combination with PGT121 and PGT126 produced additive effects. This indicates Grft could be an important combinational therapeutic.