Methods of producing cells resistant to HIV infection
Inventors
Pauza, Charles David • Li, Haishan • Lahusen, Tyler
Assignees
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Publication Number
US-12090200-B2
Publication Date
2024-09-17
Expiration Date
Abstract
The present invention relates generally to immunotherapy for preventing HIV infection in HIV-negative individuals. In particular, the methods include methods for making cells resistant to HIV and administering an immune therapy to an HIV-negative subject to prevent an HIV infection.
Core Innovation
The invention provides a method of producing cells that are resistant to HIV infection and a method of inhibiting HIV infection in an HIV-negative subject by using PBMC ex vivo treatment and genetic modification. Peripheral blood mononuclear cells (PBMC) isolated from an HIV-negative subject are contacted ex vivo with a therapeutically effective amount of a stimulatory agent and transduced with a viral delivery system encoding specific genetic elements in the form of microRNAs.
The genetic element encodes a microRNA capable of inhibiting production of chemokine receptor CCR5, a microRNA capable of inhibiting expression of HIV Vif, and a microRNA capable of inhibiting HIV Tat. The genetic element further does not encode for a microRNA capable of inhibiting an HIV gene other than Vif and Tat, and after transduction the PBMC are cultured for at least 1 day.
For the subject-level inhibition method, the invention includes immunizing the HIV-negative subject with an effective amount of a first stimulatory agent, removing leukocytes, and purifying PBMC. The method further includes contacting the PBMC ex vivo with a therapeutically effective amount of a second stimulatory agent, transducing with the viral delivery system encoding the specified microRNAs, culturing for at least 1 day, and infusing the transduced PBMC into the subject.
Claims Coverage
The provided excerpt contains two independent claims. Across these claims, the inventive features focus on ex vivo stimulatory agent treatment of PBMC, viral delivery encoding microRNAs that target CCR5, HIV Vif, and HIV Tat while avoiding microRNAs targeting other HIV genes, and culturing and, for one independent claim, infusing the transduced PBMC into an HIV-negative subject.
Ex vivo stimulatory agent contacting of HIV-negative PBMC
Contacting peripheral blood mononuclear cells (PBMC) isolated from a subject that is HIV-negative with a therapeutically effective amount of a stimulatory agent, wherein the contacting is carried out ex vivo.
Viral delivery system encoding CCR5, Vif, and Tat microRNAs without other HIV gene targeting
Transducing the PBMC ex vivo with a viral delivery system encoding at least one genetic element, wherein the at least one genetic element comprises a sequence encoding a microRNA capable of inhibiting production of chemokine receptor CCR5, a microRNA capable of inhibiting expression of HIV Vif, and a microRNA capable of inhibiting HIV Tat, and wherein the genetic element does not encode for a microRNA capable of inhibiting an HIV gene other than Vif and Tat.
Culturing transduced PBMC for at least 1 day
Culturing the transduced PBMC for at least 1 day.
Immunization with a first stimulatory agent plus ex vivo second stimulatory agent contacting
Immunizing the subject with an effective amount of a first stimulatory agent; removing leukocytes from the subject and purifying peripheral blood mononuclear cells (PBMC); and contacting the PBMC ex vivo with a therapeutically effective amount of a second stimulatory agent.
Infusion of transduced PBMC into the subject
Infusing the transduced PBMC into the subject after culturing the transduced PBMC for at least 1 day.
Taken together, the independent claims cover making HIV-resistant cells and inhibiting HIV infection by ex vivo contacting HIV-negative PBMC with a stimulatory agent, transducing the PBMC with a viral delivery system that encodes microRNAs inhibiting CCR5, HIV Vif, and HIV Tat, avoiding microRNAs against other HIV genes, followed by culturing and, in the subject-level method, infusion back into the HIV-negative subject.
Stated Advantages
Provides cells that are resistant to HIV infection.
Inhibits HIV infection in an HIV-negative subject.
Documented Applications
Preventing or inhibiting HIV infection in HIV-negative subjects using immunizing, ex vivo PBMC processing, viral transduction with CCR5/Vif/Tat-targeting microRNAs, culturing, and infusion of transduced PBMC.
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