HIV pre-immunization and immunotherapy
Inventors
Pauza, Charles David • Li, Haishan • Lahusen, Tyler • Mansfield, Gary
Assignees
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Publication Number
US-11911458-B2
Publication Date
2024-02-27
Expiration Date
Abstract
The present invention relates generally to immunization and immunotherapy for the treatment or prevention of HIV. In particular, the methods include in vivo and/or ex vivo enrichment of HIV-specific CD4+ T cells.
Core Innovation
The invention relates to a method of treating HIV infection or treating cells by obtaining peripheral blood mononuclear cells (PBMC) from a subject infected with HIV and purifying the PBMC. HIV-specific CD4+ T cells are positively selected from the PBMC and contacted ex vivo with a therapeutically effective stimulatory agent comprising a peptide, a mixture of peptides, or a vaccine.
The method further includes transducing the HIV-specific CD4+ T cells ex vivo with a viral delivery system encoding at least one genetic element, including sequences having at least 90% sequence identity with SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 97, and not comprising any small RNA targeting HIV sequences other than Vif and Tat. The transduced CD4+ T cells are cultured for at least 1 day.
For treating HIV infection in a subject, the method includes infusing the transduced HIV-specific CD4+ T cells into the subject. The described workflow includes immunizing the subject with an effective amount of a first stimulatory agent and using a second stimulatory agent ex vivo before transduction and infusion.
Claims Coverage
The partial content contains three independent claims. The claim coverage is directed to positively selecting HIV-specific CD4+ T cells, ex vivo stimulatory-agent contacting, ex vivo transduction with a viral delivery system encoding genetic elements constrained by specified sequence-identity sets, excluding small RNA targeting HIV sequences other than Vif and Tat, culturing for at least 1 day, and infusing the transduced cells into the subject.
Positively selecting HIV-specific CD4+ T cells from PBMC
Positively selecting HIV-specific CD4+ T cells from PBMC isolated from a subject infected with HIV.
Ex vivo contacting with a peptide, mixture of peptides, or vaccine
Contacting the CD4+ T-cells with a therapeutically effective amount of a stimulatory agent ex vivo, wherein the stimulatory agent comprises a peptide, a mixture of peptides, or a vaccine.
Ex vivo transduction with viral delivery system encoding genetic elements with specified sequence identity and restriction on small RNA targeting
Transducing the CD4+ T-cells ex vivo with a viral delivery system encoding at least one genetic element comprising sequences having at least 90% sequence identity with SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 97, and not comprising any small RNA targeting HIV sequences other than Vif and Tat.
Culturing the transduced HIV-specific CD4+ T cells for at least 1 day
Culturing the transduced CD4+ T-cells for at least 1 day.
Immunizing the subject with a first stimulatory agent prior to selection
Immunizing the subject with an effective amount of a first stimulatory agent; purifying peripheral blood mononuclear cells (PBMC) isolated from the subject; and positively selecting HIV-specific CD4+ T cells from the PBMC.
Infusing the transduced HIV-specific CD4+ T cells into the subject
Infusing the transduced HIV-specific CD4+ T-cells into the subject.
Treating HIV infection using an HIV vaccine and ex vivo stimulation with a second stimulatory agent
Immunizing the subject with an effective amount of an HIV vaccine; purifying peripheral blood mononuclear cells (PBMC) isolated from the subject; positively selecting HIV-specific CD4+ T cells from the PBMC; and contacting the HIV-specific CD4+ T cells ex vivo with a therapeutically effective amount of a second stimulatory agent, wherein the second stimulatory agent comprises a peptide, a mixture of peptides, or a vaccine.
Across the independent claims, the claim coverage is centered on a treatment workflow that couples positively selected HIV-specific CD4+ T cells with ex vivo stimulation and ex vivo viral transduction using a viral delivery system encoding genetic elements defined by specified sequence-identity constraints to SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 97, while restricting small RNA targeting HIV sequences to only Vif and Tat, followed by culturing for at least 1 day and infusion.
Stated Advantages
Higher fraction of modified cells.
CCR5 knockdown effectiveness.
Efficacy measurement by frequency of transduced HIV-specific CD4 T cells and/or threshold counts.
Documented Applications
Treating HIV infection in a subject using immunization, ex vivo selection and stimulation of HIV-specific CD4+ T cells, ex vivo transduction with a viral delivery system, culturing, and infusion back into the subject.
Treating cells by positively selecting HIV-specific CD4+ T cells from HIV-infected subject PBMC, ex vivo stimulation with a peptide, peptide mixture, or vaccine, ex vivo transduction with a viral delivery system encoding specified genetic elements, and culturing the transduced CD4+ T cells for at least 1 day.
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