Human immunodeficiency virus type 1 (HIV-1) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS). Since the first cases of AIDS were described in 1981, HIV-1 has become one of the most serious public health threats in the world. There are approximately 38 million people worldwide currently living with HIV-1. 28 million of these people have access to antiretroviral therapy (ART) that is highly effective in reducing viral load to undetectable levels, thereby curbing the risk of viral transmission and preventing progression to AIDS. Despite their effectiveness in suppressing HIV-1 viremia, systemic inflammation remains as a hallmark of HIV-1 infection in vivo. This persistent immune activation is often associated with non-AIDS related complications, including elevated risk of neurocognitive and cardiovascular disorders. Several different mechanisms may contribute to this chronic immune activation and inflammation in people living with HIV-1 on ART. One of the contributing factors might be HIV-1 RNA expressed from the provirus. Even though ART potently suppresses HIV-1 replication, it fails to eradicate proviruses established prior to initiation of ART. Ongoing activation of CD4+ T cells and macrophages by HIV-1 proviral transcripts might contribute to the persistent inflammation that remains even after HIV-1 suppression by ART. Previously, our laboratory has shown that induction of innate immune signaling after HIV-1 challenge of primary human dendritic cells (DCs), macrophages, or CD4+ T cells requires integration, transcription from the nascent provirus, and nuclear export of intron-containing HIV-1 RNA through the Rev-CRM1 pathway. However, these studies failed to identify the innate immune sensor of intron-containing HIV-1 RNA. Here we conducted a targeted loss-of-function screen, using shRNA-expressing lentivectors in human DCs to identify this innate immune receptor. Of the twenty-one candidate genes targeted for knockdown by shRNA, the innate immune response to HIV-1 was inhibited only by knockdown of IFIH1, MAVS, and XPO1. The effect of IFIH1 and MAVS knockdowns on HIV-1-induced immune activation was confirmed in macrophages, and rescue of the knockdown with non-targetable coding sequence showed that IFIH1 protein was required. IFIH1 mutants that are defective for interaction with MAVS blocked activation, demonstrating that MAVS acts downstream of IFIH1 in this system. Since both IFIH1 and DDX58 signal via MAVS, the specificity of HIV-1 RNA detection by IFIH1 was demonstrated by the fact that DDX58 knockdown had no effect on activation; the IFIH1-specific inhibitor Nipah virus V protein blocked the activation by HIV-1. RNA-Seq showed that IFIH1-knockdown in DCs globally disrupted the induction of IFN-1-stimulated genes. Altogether, results presented in this thesis reveal that IFIH1 is required for innate immune activation by intron-containing RNA from the HIV-1 provirus, and potentially contributes to chronic inflammation in people living with HIV-1.