Persistent IFN-I signaling associated with the HIV-1 reservoir fuels immune exhaustion and reveals therapeutic targets.

The viral reservoir established after HIV-1 infection remains the primary barrier to curing HIV. Recent studies suggest that proviral HIV-1 DNA, low-level viral transcripts, and other reservoir-derived viral products may contribute to persistent innate immune activation and type I interferon (IFN-I)-related inflammatory programs. This sustained activation drives a state of chronic immune activation, which induces and maintains exhaustion in immune cells such as CD4+ T cells. Exhaustion is characterized by loss of effector function and upregulation of inhibitory receptors (immune checkpoints), severely compromising the host's antiviral immune response. In this review, we systematically examine the molecular and cellular mechanisms by which the HIV-1 reservoir fuels immune exhaustion through the IFN-I signaling pathway. We further explore potential intervention targets along this pathway, providing a theoretical framework for the development of novel therapeutic strategies aimed at reservoir elimination or reversal of immune exhaustion.