Pro-inflammatory feedback loops define immune responses to pathogenic lentivirus infection

HIV causes chronic inflammation and AIDS in humans, though the rate of disease progression varies between individuals. Similarly, simian lentiviruses vary in their pathogenicity based on characteristics of both the host (simian species) and virus strain. Here, we profile immune responses in pig-tailed macaques infected with variants of SIV that differ in virulence to understand the immune mechanisms underlying lentiviral pathogenicity. Compared to a minimally pathogenic lentiviral variant, infection with a highly pathogenic variant results in a more delayed, broad, and sustained activation of inflammatory pathways, including an extensive global interferon signature. Conversely, individual cells infected with highly pathogenic lentivirus upregulated fewer interferon-stimulated genes at a lower magnitude, indicating that highly pathogenic lentivirus has evolved to partially escape from interferon responses. Further, we identified distinct gene co-expression patterns and cell-cell communication pathways that implicate CXCL10 and CXCL16 as important molecular drivers of inflammatory pathways specifically in response to highly pathogenic lentivirus infection. Immune responses to highly pathogenic lentivirus infection are characterized by amplifying regulatory circuits of pro-inflammatory cytokines with dense longitudinal connectivity. Our work presents a model of lentiviral pathogenicity where failures in early viral control mechanisms lead to delayed, sustained, and amplifying pro-inflammatory circuits, which has implications for other viral infections with highly variable disease courses. Overall design: Peripheral blood mononuclear cells (PBMCs) were isolated from 4 pig-tailed macaques. Two animals had been infected with minimally-pathogenic SIVMneCL8 and two animals had been infected with highly-pathogenic SIVMne170. From all animals, cells from pre-infection, and 8 post-infection time points (weeks 1, 2, 3, 4, 6, 8, 12, and 20) were thawed and processed for scRNA-seq on the Seq-Well platform. Animal key: 55 (CL8 A), 74 (CL8 B), 33 (170 A), 61 (170 B)