Griffithsin Retains Anti-HIV-1 Potency with Changes in gp120 Glycosylation and Complements Broadly Neutralizing Antibodies PGT121 and PGT126

Abstract

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 the conformational change of gp120 by mutating nearly every glycosylation site in gp120. In addition to a significant loss of Grft activity by the 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 a mutation that results in the glycan at N448 shifting to N446, indicating that the importance of individual glycans may be related to their effect on glycosylation density. Grft’s ability to alter the structure of gp120, exposing the CD4 binding site, correlated with the presence of glycosylation at N295 only in clade B strains, not clade C strains. We further demonstrate that Grft can rescue the activity of the bNAbs PGT121 and PGT126 in the event of a loss or a 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 that Grft could be an important combinational therapeutic.

Existing Antiviral Options Against SARS-CoV-2 Replication in COVID-19 Patients

“…In both in vitro and in vivo studies, it has been demonstrated that griffithsin’s identical carbohydrate domains can bind to the specific oligosaccharides on the envelope of viral glycoproteins [ 21 ]. The efficacy of this compound is through attachment to the various viral surface glycoproteins, such as HIV glycoprotein 120 and SARS-CoV spike glycoprotein, has been shown in previous studies [ 22 , 23 ]. In several previous studies, griffithsin also demonstrated an in vitro activity against SARS-CoV and MERS-CoV [ 24–26 ].…”

Detection, prevention and treatment of COVID‐19 and opportunities for nanobiotechnology

“…Griffithsin, a broad‐spectrum antiviral drug, could bind to various glycoproteins on the viral surface, such as the glycoprotein 120 of HIV and the spike glycoprotein of SARS‐CoV. 72 , 73 , 74 Due to the high similarity across the spike protein of SARS‐CoV and SARS‐CoV‐2, 75 griffithsin constitutes a potential treatment choice for COVID‐19 infections. Nafamostat has also shown an antiviral activity through targeting the host protease TMPRSS2 and inhibiting the virus−host cell membrane fusion.…”

“…Griffithsin and nafamostat could block the replication of SARS‐CoV‐2 through inhibiting the virus attachment and cell entry. Griffithsin, a broad‐spectrum antiviral drug, could bind to various glycoproteins on the viral surface, such as the glycoprotein 120 of HIV and the spike glycoprotein of SARS‐CoV 72–74 . Due to the high similarity across the spike protein of SARS‐CoV and SARS‐CoV‐2, 75 griffithsin constitutes a potential treatment choice for COVID‐19 infections.…”

A New Classification Method Based on Dynamic Ensemble Selection and its Application to Predict Variance Patterns in HIV-1 Env

“…We tested three positions in the high-mannose patch, namely positions 289, 332, and 339. These positions form part of the target sites for multiple agents that inhibit HIV-1, including antibodies 2G12, 10-1074, PGT135, PGT128, and DH270.5 [54][55][56][57][58], and the lectin microbicide griffithsin [59]. Data are composed of 1,960 amino acid sequences from 109 patients infected by HIV-1 subtype C, which is the most prevalent HIV-1 clade worldwide [60].…”