Inhibition of HIV replication through siRNA carried by CXCR4-targeted chimeric nanobody

Cunha-Santos, Catarina; Perdigão, Pedro; Martin, F. Elizabeth; Oliveira, Joana G.; Cardoso, Miguel; Manuel, Ana M.; Taveira, Nuno; Gonçalves, João

doi:10.1007/s00018-019-03334-8

Cited by 15 publications

(16 citation statements)

References 53 publications

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“…One of these studies demonstrated in vivo localization of ZFA in the brain following intraperitoneal or subcutaneous injection into a mouse model of Angelman syndrome, 76 demonstrating its capacity to cross the blood-brain barrier and modulate gene expression-a desirable feature to target potential HIV reservoirs in the central nervous system. 77 Moreover, translation of this technology into infected patients might require a receptor-targeted approach 78,79 through ZFA conjugation with ligands that direct these into the relevant cell populations, particularly, resting CD4 + T lymphocytes. Receptor-mediated delivery of zincfinger nucleases has been shown to enhance cell internalization, 80 further supporting the potential of this approach for in vivo applications.…”

Section: Discussionmentioning

confidence: 99%

Protein Delivery of Cell-Penetrating Zinc-Finger Activators Stimulates Latent HIV-1-Infected Cells

Perdigão

Cunha-Santos

Barbas

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Despite efforts to develop effective treatments for eradicating HIV-1, a cure has not yet been achieved. Whereas antiretroviral drugs target an actively replicating virus, latent, nonreplicative forms persist during treatment. Pharmacological strategies that reactivate latent HIV-1 and expose cellular reservoirs to antiretroviral therapy and the host immune system have, so far, been unsuccessful, often triggering severe side effects, mainly due to systemic immune activation. Here, we present an alternative approach for stimulating latent HIV-1 expression via direct protein delivery of cell-penetrating zinc-finger activators (ZFAs). Cys 2 -His 2 zinc-fingers, fused to a transcription activation domain, were engineered to recognize the HIV-1 promoter and induce targeted viral transcription. Following conjugation with multiple positively charged nuclear localization signal (NLS) repeats, protein delivery of a single ZFA (3NLS-PBS1-VP64) efficiently internalized HIV-1 latently infected T-lymphocytes and specifically stimulated viral expression. We show that short-term treatment with this ZFA protein induces higher levels of viral reactivation in cell line models of HIV-1 latency than those observed with gene delivery. Our work establishes protein delivery of ZFA as a novel and safe approach toward eradication of HIV-1 reservoirs.

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Section: Discussionmentioning

confidence: 99%

Protein Delivery of Cell-Penetrating Zinc-Finger Activators Stimulates Latent HIV-1-Infected Cells

Perdigão

Cunha-Santos

Barbas

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…Compared with the toxic or immune response of other carriers, nanoantibodies are safer and less likely to cause an immune response due to the absence of effector regions (Fc). According to recent research by Cunha-Santos, Catarina, etc., unlike the T-cell targeting strategy discussed above, the engineered nanoantibody targeting the CXCR4 receptor for the treatment of AIDS showed high efficiency of antibody-targeted delivery, which proved that siRNA delivery can still be achieved without using extra carriers [92].…”

Section: Other Potential Strategiesmentioning

confidence: 98%

Assembly strategy of liposome and polymer systems for siRNA delivery

Song

Hart

2021

International Journal of Pharmaceutics

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“…CXCR4 is therefore an ideal target for ACs with payloads requiring internalization to function. However, to date, only one AC construct targeted this receptor for the delivery of an anti- tat siRNA conjugated to a CXCR4 nanobody ( 70 , 80 ).…”

Section: Target Of Hiv-1 Specific Antibody Conjugatesmentioning

confidence: 99%

“…Using a nanobody against CXCR4, an anti- tat siRNA was conjugated. The construct 4M5.3X4 efficiently delivered anti- tat siRNA to CXCR4+ cell lines as well as human primary T cells, and abolished Tat-driven HIV transcription ( 70 ). This construct also marked the first time a nanobody was used as a carrier for HIV-1 AC ( Figure 4 ).…”

Section: Antibody Conjugates For Hiv-1 Curementioning

confidence: 99%

“…In cancer immunotherapy, alongside antigen density, the varying rate of internalization after AC engagement is directly linked to its efficacy ( 135 ). It is therefore not a surprise that payloads that act intracellularly were most effective when conjugated with a rapidly internalized receptor, and antibodies binding to a more proximal epitope to the plasma membrane ( 136 ), which is the case of siRNAs and toxins, respectively ( 59 , 70 ).…”

Section: Antigen Binding and Internalizationmentioning

confidence: 99%

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Antibody Conjugates for Targeted Therapy Against HIV-1 as an Emerging Tool for HIV-1 Cure

Umotoy

Taeye

2021

Front. Immunol.

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Although advances in antiretroviral therapy (ART) have significantly improved the life expectancy of people living with HIV-1 (PLWH) by suppressing HIV-1 replication, a cure for HIV/AIDS remains elusive. Recent findings of the emergence of drug resistance against various ART have resulted in an increased number of treatment failures, thus the development of novel strategies for HIV-1 cure is of immediate need. Antibody-based therapy is a well-established tool in the treatment of various diseases and the engineering of new antibody derivatives is expanding the realms of its application. An antibody-based carrier of anti-HIV-1 molecules, or antibody conjugates (ACs), could address the limitations of current HIV-1 ART by decreasing possible off-target effects, reduce toxicity, increasing the therapeutic index, and lowering production costs. Broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency against HIV-1 are currently being explored to prevent or treat HIV-1 infection in the clinic. Moreover, bNAbs can be engineered to deliver cytotoxic or immune regulating molecules as ACs, further increasing its therapeutic potential for HIV-1 cure. ACs are currently an important component of anticancer treatment with several FDA-approved constructs, however, to date, no ACs are approved to treat viral infections. This review aims to outline the development of AC for HIV-1 cure, examine the variety of carriers and payloads used, and discuss the potential of ACs in the current HIV-1 cure landscape.

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Inhibition of HIV replication through siRNA carried by CXCR4-targeted chimeric nanobody

Cited by 15 publications

References 53 publications

Protein Delivery of Cell-Penetrating Zinc-Finger Activators Stimulates Latent HIV-1-Infected Cells

Protein Delivery of Cell-Penetrating Zinc-Finger Activators Stimulates Latent HIV-1-Infected Cells

Assembly strategy of liposome and polymer systems for siRNA delivery

Antibody Conjugates for Targeted Therapy Against HIV-1 as an Emerging Tool for HIV-1 Cure

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