HIV pre-immunization and immunotherapy
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Publication Number
US-11980663-B2
Publication Date
2024-05-14
Expiration Date
Abstract
The present invention relates generally to immunization and immunotherapy for the treatment or prevention of HIV. In particular, the methods relate to in vivo and ex vivo enrichment of HIV-specific CD4 T cells. In certain embodiments, the disclosed compositions and methods can incorporate therapy in order to further enhance the HIV-specific CD4 T cells.
Core Innovation
The invention relates to a method of treating HIV infection by immunizing a subject with a therapeutically effective amount of an HIV vaccine in combination with ex vivo manipulation of immune cells. The method includes purifying peripheral blood mononuclear cells (PBMC) from the subject and contacting the PBMC ex vivo with a therapeutically effective amount of an HIV vaccine.
The core approach further transduces the PBMC ex vivo using a viral delivery system that comprises a microRNA cluster encoding microRNAs that inhibit chemokine receptor CCR5 and inhibit HIV tat gene, and optionally include microRNAs that inhibit HIV vif gene. After transduction, the transduced PBMC are cultured for about 1 to about 35 days.
Finally, the method infuses the transduced PBMC into the subject, where the subject receives a cyclophosphamide pre-treatment prior to infusing the transduced PBMC. The document also describes defining functional cure using bioassays that assess genetically modified HIV-specific CD4 T cells and their frequency or threshold after treatment, and demonstrates embodiments involving CCR5 knockdown and reduced expression of HIV tat and vif.
Claims Coverage
The disclosed subject matter is covered by two independent claims (clm-00001 and clm-00008). Across these independent claims, the inventive concept is expressed through a linked sequence of immunization, ex vivo PBMC preparation and vaccine contact, ex vivo viral transduction with a microRNA cluster targeting CCR5 and HIV genes, ex vivo culturing, and reinfusion with cyclophosphamide pre-treatment; the principal inventive features are the specific microRNA cluster targets and their use in the ex vivo transduction step.
Therapeutic HIV vaccination integrated with ex vivo PBMC handling
Immunizing a subject with a therapeutically effective amount of an HIV vaccine; purifying PBMC obtained from the subject; and contacting the PBMC ex vivo with a therapeutically effective amount of an HIV vaccine.
Ex vivo transduction with a viral delivery system encoding a microRNA cluster
Transducing the PBMC ex vivo with a viral delivery system that comprises a microRNA cluster encoding microRNAs capable of inhibiting the production of CCR5 and the production of HIV tat gene, with options including microRNAs capable of inhibiting the production of HIV vif gene, as defined for the microRNA cluster configuration.
Ex vivo culturing window and reinfusion after cyclophosphamide pre-treatment
Culturing the transduced PBMC for about 1 to about 35 days; infusing the transduced PBMC into the subject; wherein the subject receives a cyclophosphamide pre-treatment prior to infusing the transduced PBMC.
Functional targeting of chemokine receptor CCR5 and HIV tat (with optional HIV vif inhibition)
Using microRNAs within the viral delivery system such that at least one microRNA inhibits the production of chemokine receptor CCR5 and at least one microRNA inhibits the production of HIV tat gene, and optionally including additional microRNAs that inhibit production of HIV vif gene, according to the microRNA cluster configuration options.
Overall, the claims coverage centers on ex vivo PBMC preparation linked to HIV vaccine exposure, followed by viral delivery of a microRNA cluster that suppresses CCR5 and HIV tat (and optionally HIV vif), with ex vivo culturing and reinfusion supported by cyclophosphamide pre-treatment.
Stated Advantages
Enables treatment of HIV infection/HIV in an HIV+ subject using an HIV vaccine combined with ex vivo transduced PBMC.
Documented Applications
Treating HIV infection by immunizing a subject with an HIV vaccine, transducing ex vivo PBMC with a viral delivery system encoding microRNAs that inhibit CCR5 and HIV genes, and infusing the transduced PBMC following cyclophosphamide pre-treatment.
Assessing functional cure using bioassays that measure frequency/threshold of genetically modified HIV-specific CD4 T cells after treatment.
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