CARD8 inflammasome sensitization through DPP9 inhibition enhances NNRTI-triggered killing of HIV-1-infected cells

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) induce pyroptosis of HIV-1 infected CD4+ T cells through induction of intracellular viral protease activation, which then activates the CARD8 inflammasome. Due to high concentrations of NNRTIs being required for efficient CARD8 activation and elimination of HIV-1-infected cells, it is important to elucidate ways to sensitize the CARD8 inflammasome to NNRTI-induced activation. We show that this sensitization can be done through chemical inhibition of the CARD8 negative regulator DPP9. DPP9 inhibitor Val-boroPro (VbP) can act synergistically with NNRTIs to increase their efficacy in killing HIV-1-infected cells. We also show that VbP is able to partially overcome issues with NNRTI resistance and is capable of killing infected cells without the presence of NNRTIs. This offers a promising strategy for enhancing NNRTI efficacy in elimination of HIV-1 reservoirs in patients.

Beyond Inhibition: A Novel Strategy of Targeting HIV-1 Protease to Eliminate Viral Reservoirs

“…Some obstacles toward implementation of this strategy include the high concentrations of NNRTIs required for CARD8 inflammasome activation in HIV-1-infected cells and the fact that NNRTIs bind human serum proteins, reducing their bioavailability in vivo [74]. A recent preprint suggests that CARD8 sensitization through inhibition of DPP9, a negative regulator of CARD8, can overcome these obstacles and enhance NNRTI-triggered killing of HIV-1-infected cells [75]. Furthermore, drug screening for compounds that more efficiently trigger Gag-Pol dimerization and premature PR activation is a promising strategy to identify novel antivirals that can efficiently induce CARD8 inflammasome-dependent killing of HIV-1-infected cells with few side effects.…”

Inflammasomes in Human Immunodeficiency Virus Type 1 Infection

“…Based on this concept, our group recently found that DPP9 inhibition reduces the threshold concentration of NNRTIs needed to trigger pyroptosis in HIV-infected cells. [ 65 ] Another major obstacle for targeting the inflammasome for the treatment of HIV-1 infection is cytokine release during inflammasome activation. However, it is generally accepted that CD4 + T cells do not secrete the inflammatory cytokines IL-1β or IL-18.…”