A bivalent recombinant protein inactivates HIV-1 by targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2 domains

Lu, Lu; Pan, Chungen; Li, Yuan; Liang, Hong; He, Wei; Jiang, Shibo

doi:10.1186/1742-4690-9-104

Cited by 61 publications

(74 citation statements)

References 58 publications

(63 reference statements)

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“…30 To avoid this problem, we used HIV-1 particles pelleted from culture supernatants by a PEG-based virus precipitation solution 31 in all the experiments.…”

Section: Hiv-1 Impairs Hrpe Barrier Function S Tan Et Almentioning

confidence: 99%

HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy

Tan

Duan

Xun

et al. 2014

Laboratory Investigation

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The breakdown of human retinal pigment epithelial (HRPE) barrier is considered as the etiology of retinopathy, which affects the quality of life of HIV/AIDS patients. Here we demonstrate that HIV-1 could directly impair HRPE barrier function, which leads to the translocation of HIV-1 and bacteria. HRPE cells (D407) were grown to form polarized, confluent monolayers and treated with different HIV-1 infectious clones. A significant increase of monolayer permeability, as measured by trans-epithelial electrical resistance (TEER) and apical-basolateral movements of sodium fluorescein, was observed. Disrupted tightness of HRPE barrier was associated with the downregulation of several tight junction proteins in D407 cells, including ZO-1, Occludin, Claudin-1, Claudin-2, Claudin-3, Claudin-4, and Claudin-5, after exposure to HIV-1, without affecting the viability of cells. HIV-1 gp120 was shown to participate in the alteration of barrier properties, as evidenced by decreased TEER and weakened expression of tight junction proteins in D407 monolayers after exposure to pseudotyped HIV-1, UV-inactivated HIV-1, and free gp120, but not to an envelope (Env)-defective mutant of HIV. Furthermore, exposure to HIV-1 particles could induce the release of pro-inflammatory cytokines in D407, including IL-6 and MCP-1, both of which downregulated the expression of ZO-1 in the HRPE barrier. Disrupted HRPE monolayer allowed translocation of HIV-1 and bacteria across the epithelium. Overall, these findings suggest that HIV-1 may exploit its Env glycoprotein to induce an inflammatory state in HRPE cells, which could result in impairment of HRPE monolayer integrity, allowing virus and bacteria existing in ocular fluids to cross the epithelium and penetrate the HRPE barrier. Our study highlights the role of HIV-1 in the pathogenesis of HIV/AIDS-related retinopathy and suggests potential therapeutic targets for this ocular complication.

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“…30 To avoid this problem, we used HIV-1 particles pelleted from culture supernatants by a PEG-based virus precipitation solution 31 in all the experiments.…”

Section: Hiv-1 Impairs Hrpe Barrier Function S Tan Et Almentioning

confidence: 99%

HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy

Tan

Duan

Xun

et al. 2014

Laboratory Investigation

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“…At the same time, 2DLT acts as a dual barrier against HIV infection by first inactivating HIV-1 virions away from cells and then blocking HIV-1 entry on the target cell surface [72]. Synergistic effect resulting from combinations of this bifunctional recombinant protein with different antiretroviral drugs has been observed in a study [73].…”

Section: Resultsmentioning

confidence: 95%

“…A bivalent HIV-1 antagonist 2DLT [72] targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2 domains is an example of novel potent HIV-1 inhibitor that prevents the HIV-1 binding to CD4 and fusion of the virus with a cell membrane. At the same time, 2DLT acts as a dual barrier against HIV infection by first inactivating HIV-1 virions away from cells and then blocking HIV-1 entry on the target cell surface [72].…”

Section: Resultsmentioning

confidence: 99%

Computational discovery of novel HIV-1 entry inhibitors based on potent and broad neutralizing antibody VRC01

Andrianov

Kashyn

Tuzikov

2015

Journal of Molecular Graphics and Modelling

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“…Lu et al 46 . have developed a similar inhibitor by linking sCD4 to a different fusion inhibitor, T1144, and analyzed the mechanism of inhibition in detail.…”

Section: Discussionmentioning

confidence: 99%

Further Characterization of the Bifunctional HIV Entry Inhibitor sCD4-FI T45

Falkenhagen

Joshi

2017

Molecular Therapy - Nucleic Acids

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HIV entry into target cells is a highly sequential and time-sensitive process. In recent years, potent HIV Env-targeting antibodies, such as VRC01, have been identified. However, antibodies bind only to a single epitope, and mutations that confer resistance to antibody-mediated inhibition of HIV entry have been detected. In contrast, HIV cannot escape from binding to soluble CD4 (sCD4) without a fitness disadvantage. sCD4 has the unique ability to induce conformational changes within the HIV envelope glycoproteins (Env) that allow fusion inhibitors to bind. We have previously linked sCD4 to the fusion inhibitor FIT45 (sCD4-FIT45) and examined delivery of the bifunctional entry inhibitor via gene therapy. Here, we extend our studies and analyze the ability of sCD4-FIT45 to inhibit HIV Env-mediated cell fusion and HIV entry of several primary isolates. sCD4-FIT45 inhibited both cell fusion and HIV entry with remarkable antiviral activity. The mean 50% inhibitory concentrations (IC50) for sCD4-FIT45 were <0.2 μg/mL in both assays. Importantly, inhibition by sCD4-FIT45 was more potent than by VRC01, sCD4, or the previously described bifunctional protein sCD4-scFv17b. In contrast to sCD4, sCD4-FIT45 as well as VRC01 and sCD4-scFv17b did not mediate cell fusion between HIV Env+ and CD4−CCR5+ cells. The results presented here provide further evidence for the testing of sCD4-FIT45 and development of bifunctional proteins based on the sCD4-fusion inhibitor architecture.

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A bivalent recombinant protein inactivates HIV-1 by targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2 domains

Cited by 61 publications

References 58 publications

HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy

HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy

Computational discovery of novel HIV-1 entry inhibitors based on potent and broad neutralizing antibody VRC01

Further Characterization of the Bifunctional HIV Entry Inhibitor sCD4-FI T45

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