The Role of Inflammasome Activation in Early HIV Infection

Abstract

The inflammasome pathway is an important arm of the innate immune system that provides antiviral immunity against many viruses. The main pathways involved in virus infections include the NLRP3, IFI16, and AIM2 pathways. However, a succinct understanding of its role in HIV is not yet well elucidated. In this review, we showed that NLRP3 inflammasome activation plays a vital role in inhibiting HIV entry into target cells via the purinergic pathway; IFI16 detects intracellular HIV ssDNA, triggers interferon I and III production, and inhibits HIV transcription; and AIM2 binds to HIV dsDNA and triggers acute inflammation and pyroptosis. Remarkably, by understanding these mechanisms, new therapeutic strategies can be developed against the disease.

Figure 1

An illustration of the NLRP3 activation in HIV infection, and how HIV evades the NLRP3 inflammasome pathway. HIV infects target cells by interacting with CD4 receptors and coreceptors CXCR4/CCR5, which leads to the activation of the purinergic pathway via an increase in extracellular ATP and potassium ion [K+] efflux. Interaction between the activated purinergic receptor (P2Y2) and NLRP3 leads to activation of NLRP3 inflammasome which triggers acute inflammation, pyroptosis (via Gasdermin D), and inhibition of HIV entry. However, HIV evades the NLRP3 inflammasome pathway by activating the release of E3 ubiquitin ligase which ubiquitinates NLRP3 leading to proteasomal degradation. Also, abortive HIV infection of resting CD4 T cells triggers NLRP3-mediated pyroptosis which accounts for majority of CD4 T cell depletion and sustained inflammation.

Figure 2

An illustration of the various mechanisms and pathways triggered by activated IFI16 in an HIV infection. (A) The activation of the STINK-TBK1-IRF3/7 pathway by IFI16 after the sensing of retroviral DNA intermediates or ssDNA. (B) The activation of the IFI16 inflammasome and resulting cell death due to the accumulation of incomplete DNA reverse transcripts of HIV during an abortive HIV infection. (C) Restriction of HIV-1 replication by IFI16 independently of immune sensing through the binding and inhibition of the host transcription factor Sp1.

Figure 3

Illustration of the AIM2 inflammasome pathway activation during an HIV infection. The figure summarizes the stepwise genomic switching of the HIV upon cell entry. The AIM2 recognizes the viral dsDNA and interacts with the ASC. Activated ASC further recruits and activate the caspase 1 enzyme which triggers the process of pyroptosis (cell death).