Role of the CARD8 inflammasome in HIV pathogenesis

Abstract

Human immunodeficiency virus (HIV) continues to be a significant global health challenge despite decades of research and advances in treatment. Substantial gaps in our understanding of the mechanisms of HIV pathogenesis and the host immune responses still exist. The interaction between HIV and these immune responses is pivotal in the disease progression to acquired immunodeficiency syndrome (AIDS). Recently, the caspase recruitment domain-containing protein 8 (CARD8) inflammasome has emerged as a crucial factor in orchestrating innate immune responses to HIV infection and exerting a substantial impact on viral pathogenesis. CARD8 restricts viral replication by detecting the activity of HIV protease. Conversely, it also contributes to the depletion of CD4⁺ T cells, a key feature of disease progression towards AIDS. The purpose of this review is to summarize the role of the CARD8 inflammasome in HIV pathogenesis, delving into its mechanisms of action and potential implications for the development of therapeutic strategies.

Fig. 1

Mechanism of CARD8 activation by HIV Upon entering resting CD4⁺ T cells, the HIV protease encapsulated within incoming viral particles immediately triggers the CARD8 inflammasome. This protease cleaves the N-terminus of CARD8, generating an unstable new N-terminus marked for proteasomal degradation. Consequently, the biologically active C-terminal UPA-CARD fragment of CARD8 is liberated, initiating the inflammasome assembly. This leads to the recruitment and activation of CASP1, ultimately resulting in GSDMD-dependent pyroptosis of the resting CD4⁺ T cells.