Adeno-Associated Virus Delivery of Anti-HIV Monoclonal Antibodies Can Drive Long-Term Virologic Suppression

Martinez-Navío, José M.; Fuchs, Sebastian; Pantry, Shara N.; Lauer, William; Duggan, Natasha N; Keele, Brandon F.; Rakasz, Eva G.; Gao, Guangping; Lifson, Jeffrey D.; Desrosiers, Ronald C.

doi:10.1016/j.immuni.2019.02.005

Cited by 104 publications

(94 citation statements)

References 61 publications

(74 reference statements)

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“…For more examples on long-term delivery with AAV of hemophilia factors, please see the following references (61)(62)(63)(64)(65)(66)(67)(68). The long-term delivery described in our report here is significant as the first such report for very long-term delivery of an antibody, particularly given the serious difficulties that have been encountered when AAV has been used to deliver antibodies that are significantly diverged from germ line or contain unusual features (1,14,28,30,31). The findings give hope that long-term delivery of therapeutic antibodies via AAV can be consistently achieved if the ADA problem can be overcome.…”

Section: Discussionmentioning

confidence: 84%

“…Due to the difficulties associated with proving curative and/or protective interventions (51), additional tests were considered such as in vivo CD8+ T-cell depletion and attempts at adoptive transfer of infection to naïve rhesus macaques. However, we did not want to put this precious monkey at any risk with the CD8 depletion; and, surprisingly, adoptive transfer may not be as sensitive as one would think (14). The absence of an ADA response is almost certainly a key factor in the continuous production of the transgene product in monkey 84-05.…”

Section: Discussionmentioning

confidence: 98%

“…Like the Miami monkey (14,77,78), monkey 84-05 stands out as a shining example of what is possible in the realm of AAV delivery of monoclonal antibodies in the fight against HIV. The Miami monkey has maintained high levels of two anti-HIV monoclonal antibodies and complete virologic suppression of SHIV infection for more than 4 years of followup without any repeated administrations and without any other antiviral therapies.…”

Section: Discussionmentioning

confidence: 99%

“…One potentially important application of the AAV system is the delivery of broadly neutralizing antibodies as a gene therapy approach against HIV (1,(11)(12)(13)(14). For that purpose, recombinant AAVs encoding neutralizing antibodies are inoculated into the host and the antibody or antibodies of interest will then be directly expressed from the transduced cells.…”

Section: Introductionmentioning

confidence: 99%

“…These antibodies have been extensively characterized in the laboratory and some have moved to clinical trials, where they have shown activity (18)(19)(20)(21)(22). They have the potential to prevent infection and also serve as a therapeutic approach complementing or even substituting antiretroviral drugs (11,14,18,(20)(21)(22)(23)(24)(25). Importantly, the use of AAV voids the need for repeated administrations of purified antibody to maintain therapeutic levels in circulation.…”

Section: Introductionmentioning

confidence: 99%

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Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

et al. 2020

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Long-term delivery of anti-HIV monoclonal antibodies using adeno-associated virus (AAV) holds promise for the prevention and treatment of HIV infection. We previously reported that after receiving a single administration of AAV vector coding for anti-SIV antibody 5L7, monkey 84-05 achieved high levels of AAV-delivered 5L7 IgG1 in vivo which conferred sterile protection against six successive, escalating dose, intravenous challenges with highly infectious, highly pathogenic SIVmac239, including a final challenge with 10 animal infectious doses (1). Here we report that monkey 84-05 has successfully maintained 240-350 µg/ml of anti-SIV antibody 5L7 for over 6 years. Approximately 2% of the circulating IgG in this monkey is this one monoclonal antibody. This monkey generated little or no anti-drug antibodies (ADA) to the AAV-delivered antibody for the duration of the study. Due to the nature of the high-dose challenge used and in order to rule out a potential low-level infection not detected by regular viral loads, we have used ultrasensitive techniques to detect cell-associated viral DNA and RNA in PBMCs from this animal. In addition, we have tested serum from 84-05 by ELISA against overlapping peptides spanning the whole envelope sequence for SIVmac239 (PepScan) and against recombinant p27 and gp41 proteins. No reactivity has been detected in the ELISAs indicating the absence of naturally arising anti-SIV antibodies; moreover, the ultrasensitive cell-associated viral tests yielded no positive reaction. We conclude that macaque 84-05 was effectively protected and remained uninfected. Our data show that durable, continuous antibody expression can be achieved after one single administration of AAV and support the potential for lifelong protection against HIV from a single vector administration.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

et al. 2020

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Structural characterization of the porcine adeno‐associated virus Po1 capsid protein binding to the nuclear trafficking protein importin alpha

2021

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Adeno‐associated viruses (AAVs) are key vectors for gene therapy; thus, many aspects of their cell transduction pathway have been revealed in detail. However, the specific mechanisms AAV virions use to enter the host nucleus remain largely unresolved. We therefore aimed to reveal the structural interactions between the AAV capsid (Cap) protein and the nuclear transport protein importin alpha (IMPα). A putative nuclear localization sequence (NLS) in the virion protein 1 capsid protein of the porcine AAV Po1 was identified. This region was complexed with IMPα and a structure solved at 2.26 Å. This is the first time that an NLS of AAV Cap complexed with IMPα has been determined structurally. Our results support the findings that AAV capsids enter the nucleus through binding the nuclear import adapter IMPα.

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Viral Nanoparticles‐Mediated Delivery of Therapeutic Cargo

Zanganeh

Doroudian

Nowzari

et al. 2023

Advanced Therapeutics

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The rapid advancement of nanotechnology in recent years has opened new avenues of investigation for biomedical sciences. Viral nanoparticles (VNPs) are formulated from plant viruses, mammalian viruses, or bacteriophages. Based on their structure, viruses, and synthetic carriers have been utilized to design bio‐inspired nanocarriers, which serve as building blocks for innovative therapeutic applications. Scientists can chemically or genetically engineer VNPs to encompass various properties, such as enhancing their functionalization with therapeutic molecules and imaging reagents, enabling targeted delivery to specific ligands. The implementation of these novel nanocarrier platforms can revolutionize treatments for cancer, infectious diseases, and chronic illnesses. The primary goal of drug delivery systems is to localize cargo to the specific target site, increasing therapeutic benefits and minimizing off‐target effects. This review critically evaluates the major virus species used as nanocarriers, their applications in therapeutics, and their advantages and disadvantages.

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Adeno-Associated Virus Delivery of Anti-HIV Monoclonal Antibodies Can Drive Long-Term Virologic Suppression

Cited by 104 publications

References 61 publications

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

Structural characterization of the porcine adeno‐associated virus Po1 capsid protein binding to the nuclear trafficking protein importin alpha

Viral Nanoparticles‐Mediated Delivery of Therapeutic Cargo

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