Latency reversal plus natural killer cells diminish HIV reservoir in vivo

Abstract

HIV is difficult to eradicate due to the persistence of a long-lived reservoir of latently infected cells. Previous studies have shown that natural killer cells are important to inhibiting HIV infection, but it is unclear whether the administration of natural killer cells can reduce rebound viremia when anti-retroviral therapy is discontinued. Here we show the administration of allogeneic human peripheral blood natural killer cells delays viral rebound following interruption of anti-retroviral therapy in humanized mice infected with HIV-1. Utilizing genetically barcoded virus technology, we show these natural killer cells efficiently reduced viral clones rebounding from latency. Moreover, a kick and kill strategy comprised of the protein kinase C modulator and latency reversing agent SUW133 and allogeneic human peripheral blood natural killer cells during anti-retroviral therapy eliminated the viral reservoir in a subset of mice. Therefore, combinations utilizing latency reversal agents with targeted cellular killing agents may be an effective approach to eradicating the viral reservoir.

Learning to Be Elite: Lessons From HIV-1 Controllers and Animal Models on Trained Innate Immunity and Virus Suppression

“…In HIV-1 infected humanized mice, ILC1 and ILC3 are depleted in lymphoid tissues by type 1 IFN produced by pDCs ( 59 , 60 ). Recently, Kim and colleagues ( 89 ) demonstrated that infusion of allogenic human NK cells in HIV-1-infected humanized mice can delay HIV-1 viral rebound after ART interruption. Additionally, animals who received allogenic NK cell transfer displayed reduced diversity in HIV-1 species, highlighting the significance of NK cells in HIV-1 control in this model.…”

Ansellone J, a Potent in Vitro and ex Vivo HIV-1 Latency Reversal Agent Isolated from a Phorbas sp. Marine Sponge

“…sesterterpenoid, ansellone J ( 6 ), was further evaluated for HIV latency reversal in a primary cell context using CD4+ T cells obtained directly from four cART-suppressed donors with HIV (Figure ). Ansellone J ( 6 ) induced HIV latency reversal at levels similar to prostratin ( 3 ) ex vivo , but at a 10-fold lower concentration, making 6 a promising lead compound for the development of synthetic LRAs as clinical trial candidates to test the potential of a “shock and kill” approach to a sterilizing cure for HIV-1 infections …”

Advances in HIV-1-specific chimeric antigen receptor cells to target the HIV-1 reservoir

“…Administration of allogeneic human peripheral blood NK cells delayed viral rebound following interruption of ART in humanized mice infected with HIV-1. 72 A kick and kill strategy comprised of the protein kinase C modulator SUW133 and allogeneic human peripheral blood NK cells during ART eliminated the viral reservoir in a subset of these mice. SMU-Z1, a novel small-molecule TLR1/2 agonist enhanced HIV-1 transcription and promoted NK cell-mediated inhibition of HIV-1 infected autologous CD4 + T cells.…”