Synergistic inhibition of cell-to-cell HIV-1 infection by combinations of single chain variable fragments and fusion inhibitors

Alam, Mohammad Mamun; Kuwata, Takeo; Tanaka, Kazuki; Alam, Muntasir; Takahama, Shokichi; Shimura, Kazuya; Matsuoka, Masao; Fukuda, Natsuki; Morioka, Hiroshi; Tamamura, Hirokazu; Matsushita, Shuzo

doi:10.1016/j.bbrep.2019.100687

Cited by 3 publications

(2 citation statements)

References 41 publications

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“…By the use of the NFκB-inhibitor Minocyclin, cell fusion has been markedly reduced [129]. Additional cell fusion inhibitors have been used to inhibit HIV cell-free and cell-cell infections [130][131][132][133]. In summary, cell fusion is an important process in tissue regeneration, but it also might lead to the development of different diseases, if this process is dysregulated.…”

Section: Cell Fusion and Stem Cellsmentioning

confidence: 99%

The Role of MSCs and Cell Fusion in Tissue Regeneration

Dörnen

Dittmar

2021

IJMS

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Regenerative medicine is concerned with the investigation of therapeutic agents that can be used to promote the process of regeneration after injury or in different diseases. Mesenchymal stem/stromal cells (MSCs) and their secretome – including extracellular vesicles (EVs) are of great interest, due to their role in tissue regeneration, immunomodulatory capacity and low immunogenicity. So far, clinical studies are not very conclusive as they show conflicting efficacies regarding the use of MSCs. An additional process possibly involved in regeneration might be cell fusion. This process occurs in both a physiological and a pathophysiological context and can be affected by immune response due to inflammation. In this review the role of MSCs and cell fusion in tissue regeneration is discussed.

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Section: Cell Fusion and Stem Cellsmentioning

confidence: 99%

The Role of MSCs and Cell Fusion in Tissue Regeneration

Dörnen

Dittmar

2021

IJMS

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“…This may be especially true for epitopes in close proximity such as the V2 and V3, or V3 and CD4bs. A recent study demonstrated that scFv targeting the V3 and CD4bs could display synergy when combined with fusion inhibitors ( 37 ).…”

Section: Introductionmentioning

confidence: 99%

Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth

et al. 2021

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Broadly neutralizing antibodies (bNAbs) are currently being assessed in clinical trials for their ability to prevent HIV infection. Single chain variable fragments (scFv) of bNAbs have advantages over full antibodies as their smaller size permits improved diffusion into mucosal tissues and facilitates vector-driven gene expression. We have previously shown that scFv of bNAbs individually retain significant breadth and potency. Here we tested combinations of five scFv derived from bNAbs CAP256-VRC26.25 (V2-apex), PGT121 (N332-supersite), 3BNC117 (CD4bs), 8ANC195 (gp120-gp41 interface) and 10E8v4 (MPER). Either two or three scFv were combined in equimolar amounts and tested in the TZM-bl neutralization assay against a multiclade panel of 17 viruses. Experimental IC50 and IC80 data were compared to predicted neutralization titers based on single scFv titers using the Loewe additive and the Bliss-Hill model. Like full-sized antibodies, combinations of scFv showed significantly improved potency and breadth compared to single scFv. Combinations of two or three scFv generally followed an independent action model for breadth and potency with no significant synergy or antagonism observed overall although some exceptions were noted. The Loewe model underestimated potency for some dual and triple combinations while the Bliss-Hill model was better at predicting IC80 titers of triple combinations. Given this, we used the Bliss-Hill model to predict the coverage of scFv against a 45-virus panel at concentrations that correlated with protection in the AMP trials. Using IC80 titers and concentrations of 1μg/mL, there was 93% coverage for one dual scFv combination (3BNC117+10E8v4), and 96% coverage for two of the triple combinations (CAP256.25+3BNC117+10E8v4 and PGT121+3BNC117+10E8v4). Combinations of scFv, therefore, show significantly improved breadth and potency over individual scFv and given their size advantage, have potential for use in passive immunization.

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Single-Chain Variable Fragments of Broadly Neutralizing Antibodies Prevent HIV Cell-Cell Transmission

Dorsten

Reh

Trkola

et al. 2022

J Virol

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Broadly neutralizing antibodies (bNAbs) are able to prevent HIV infection following passive administration. Single-chain variable fragments (scFv) may have advantages over IgG as their smaller size permits improved diffusion into mucosal tissues. We have previously shown that scFv of bNAbs retain significant breadth and potency against cell-free viral transmission in a TZM-bl assay. However, scFv have not been tested for their ability to block cell-cell transmission, a model in which full-sized bNAbs lose potency. We tested 4 scFv (CAP256.25, PGT121, 3BNC117 and 10E8v4) compared to IgG, in free-virus and cell-cell neutralization assays in A3.01 cells, against a panel of seven heterologous viruses. We show that free-virus neutralization titers in the TZM-bl and A3.01 assays were not significantly different, and confirm that scFv show a 1 to 32-fold reduction in activity in the cell-free model, compared to IgG. However, whereas IgG show 3.4 to 19-fold geometric mean potency loss in cell-cell neutralization compared to free-virus transmission, scFv had more comparable activity in the two assays, with only a 1.3 to 2.3-fold reduction. Geometric mean IC 50 of scFv for cell-cell transmission ranged from 0.65 μg/ml (10E8v4) to 2.3 μg/ml (3BNC117) with IgG and scFv neutralization showing similar potency against cell-associated transmission. Therefore, despite the reduced activity of scFv in cell-free assays, their retention of activity in the cell-cell format may make scFv useful for the prevention of both modes of transmission in HIV prevention studies. Importance Broadly neutralizing antibodies (bNAbs) are a major focus for passive immunization against HIV, with the recently concluded HVTN AMP (Antibody Mediated Protection) trial providing proof of concept. Most studies focus on cell-free HIV, however cell-associated virus may play a significant role in HIV infection, pathogenesis and latency. Single-chain variable fragments (scFv) of antibodies may have increased tissue penetration, and reduced immunogenicity. We previously demonstrated that scFv of four HIV-directed bNAbs (CAP256-VRC26.25, PGT121, 3BNC117 and 10E8v4) retain significant potency and breadth against cell-free HIV. As some bNAbs have been shown to lose potency against cell-associated virus, we investigated the ability of bNAb scFv to neutralize this mode of transmission. We demonstrate that unlike IgG, scFv of bNAbs are able to neutralize cell-free and cell-associated virus with similar potency. These scFv, which show functional activity in the therapeutic range, may therefore be suitable for further development as passive immunity for HIV prevention.

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Synergistic inhibition of cell-to-cell HIV-1 infection by combinations of single chain variable fragments and fusion inhibitors

Cited by 3 publications

References 41 publications

The Role of MSCs and Cell Fusion in Tissue Regeneration

The Role of MSCs and Cell Fusion in Tissue Regeneration

Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth

Single-Chain Variable Fragments of Broadly Neutralizing Antibodies Prevent HIV Cell-Cell Transmission

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