Innate Immune Regulation in HIV Latency

Abstract

Innate immunity and type 1 interferon (IFN) defenses are critical for early control of HIV-1 infection within CD4+ T cells. Despite these defenses, some acutely infected cells silence viral transcription to become latently infected and form the HIV-1 reservoir in vivo. Latently infected cells persist through antiretroviral therapy (ART) and are a major barrier to HIV-1 cure. Here, I evaluated innate immunity and type 1 IFN signaling in multiple CD4+ T cell models of HIV-1 latency, including established latent cell lines, Jurkat cells latently infected with a reporter virus, and a primary CD4+ T cell model of virologic suppression. I found that while latently infected T cell lines have functional RNA sensing and IFN signaling pathways, they fail to induce specific interferon-stimulated genes (ISGs) in response to innate immune activation or type 1 IFN treatment. Jurkat cells latently infected with a fluorescent reporter HIV-1 similarly demonstrate attenuated responses to type 1 IFN. Using bulk and single-cell RNA sequencing I applied a functional genomics approach to define ISG expression dynamics in latent HIV-1 infection, including HIV-infected ART-suppressed primary CD4+ T cells. My observations indicate that HIV-1 latency and viral suppression each link with cell-intrinsic defects in ISG induction, though the specific defects vary among latency models and clones. In this study I identify a set of ISGs for consideration as latency restriction factors whose expression and function could possibly mitigate establishment of latent HIV-1 infection.