Rev-dependent lentiviral vector targeting HIV reservoirs
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Solution Overview
Problem
Current antiretroviral therapies fail to selectively eliminate HIV reservoirs, leading to persistent viral loads and eventual viral rebound upon treatment cessation, as they do not target and eliminate latent and active reservoirs effectively, particularly in cells like resting CD4 T cells and macrophages.
Innovation Solution
A Rev-dependent vector system, which can deliver therapeutic genes or function independently to induce apoptosis or inhibit viral transcription, is used to target and eliminate HIV-infected cells by expressing genes like HSV-thymidine kinase or TRAF6, or functioning without them, to reduce viral reservoirs and prevent rebound.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If combination antiretroviral therapy (cART) is used to inhibit viral replication, then plasma viremia is reduced to undetectable levels, but viral reservoirs persist and lead to viral rebound upon treatment cessation
Solution Approach 1:
The patent introduces a Rev-dependent lentiviral vector as an intermediary therapeutic agent that selectively targets and eliminates HIV reservoirs. This vector uses the HIV Rev protein itself as a mediator to deliver toxic payloads only to infected cells, converting the viral protein into a tool for viral eradication rather than replication
Solution Approach 2:
The invention converts the harmful HIV Rev protein into a beneficial targeting mechanism. By making the therapeutic vector's expression dependent on Rev, the system uses the viral protein's presence as a marker to selectively deliver cytotoxic agents only to infected cells, turning the virus's own machinery against it
2Reliability
If Rev-dependent lentiviral vectors are used to target infected cells, then viral reservoirs are eliminated, but the system requires HIV Rev protein presence to function
Solution Approach 1:
The system dynamically adapts its activation state based on the presence of HIV Rev protein. The vector remains dormant in uninfected cells and only activates in the presence of Rev, creating a dynamic response that automatically targets infected cells without requiring external activation signals or coordination with antiretroviral therapy regimens
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The Rev-dependent vector system effectively reduces and eliminates HIV/SIV viral rebound and reservoirs, achieving long-lasting remission and potentially a functional cure by inducing apoptosis in infected cells and inhibiting viral production, even in the absence of antiretroviral therapy.
Implementation Method 1
expressing genes like HSV-thymidine kinase or TRAF6, or functioning without them, to reduce viral reservoirs and prevent rebound
Implementation Method 2
inhibiting viral transcription, is used to target and eliminate HIV-infected cells by expressing genes like HSV-thymidine kinase or TRAF6
Data Source
AI summary
Persistence of HIV in anatomic sanctuary sites such as the brain prevents viral eradication. Although combination antiretroviral therapy (cART) inhibits viral replication to undetectable level by standard clinical assay, it does not selectively eliminate virus reservoirs. To target HIV reservoirs, the present inventor developed an HIV Rev-dependent lentiviral vector carrying a series of therapeutic genes, such as diphtheria toxin, anthrolysin O from Bacillus anthracis, human TRAF6, or the herpes simplex 1 virus thymidine kinase gene (HSV-tk). The present disclosure provides the Rev-dependent vectors for targeting viral reservoir in a SIV/rhesus macaque model. SIV-infected rhesus macaques were first treated with cART for over 6 months starting 12 weeks post infection, followed by injections with viral particles assembled from a SIV Rev-dependent vector carrying HSV-tk. Following particle injection, animals were further treated briefly (two weeks) with ganciclovir (GCV), which induces the killing of SIV+, HSV-tk expressing cells. cART was terminated following the GCV treatment, and there was observed a partial control of viral rebound over a period of 4 months after cART cessation. The animal was further treated with additional Rev-dependent vector particles, and viral load was diminished to the undetectable level for over 1 year in the absence of any treatment. These results suggest that the Rev-dependent vector, with or without a functional gene, has the potential to diminish viral reservoirs in vivo and can offer a cure of functional cure of HIV/SIV infection.