Pro-inflammatory feedback loops define immune responses to pathogenic Lentivirus infection.

BACKGROUND: The Lentivirus human immunodeficiency virus (HIV) causes chronic inflammation and AIDS in humans, with variable rates of disease progression between individuals driven by both host and viral factors. Similarly, simian lentiviruses vary in their pathogenicity based on characteristics of both the host species and the virus strain, yet the immune underpinnings that drive differential Lentivirus pathogenicity remain incompletely understood. METHODS: We profile immune responses in a unique model of differential lentiviral pathogenicity where pig-tailed macaques are infected with highly genetically similar variants of SIV that differ in virulence. We apply longitudinal single-cell transcriptomics to this cohort, along with single-cell resolution cell-cell communication techniques, to understand the immune mechanisms underlying lentiviral pathogenicity. RESULTS: 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 identify 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. CONCLUSIONS: 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 in turn drives disease progression.

Differential virus host-ranges of the Fuselloviridae of hyperthermophilic Archaea: implications for evolution in extreme environments.

An emerging model for investigating virus-host interactions in hyperthermophilic Archaea is the Fusellovirus-Sulfolobus system. The host, Sulfolobus, is a hyperthermophilic acidophile endemic to sulfuric hot springs worldwide. The Fuselloviruses, also known as Sulfolobus Spindle-shaped Viruses (SSVs), are "lemon" or "spindle"-shaped double-stranded DNA viruses, which are also found worldwide. Although a few studies have addressed the host-range for the type virus, Sulfolobus Spindle-shaped Virus 1 (SSV1), using common Sulfolobus strains, a comprehensive host-range study for SSV-Sulfolobus systems has not been performed. Herein, we examine six bona fide SSV strains (SSV1, SSV2, SSV3, SSVL1, SSVK1, SSVRH) and their respective infection characteristics on multiple hosts from the family Sulfolobaceae. A spot-on-lawn or "halo" assay was employed to determine SSV infectivity (and host susceptibility) in parallel challenges of multiple SSVs on a lawn of a single Sulfolobus strain. Different SSVs have different host-ranges with SSV1 exhibiting the narrowest host-range and SSVRH exhibiting the broadest host range. In contrast to previous reports, SSVs can infect hosts beyond the genus Sulfolobus. Furthermore, geography does not appear to be a reliable predictor of Sulfolobus susceptibility to infection by any given SSV. The ability for SSVs to infect susceptible Sulfolobus host does not appear to change between 65°C and 88°C (physiological range); however, very low pH appears to influence infection. Lastly, for the virus-host pairs tested the Fusellovirus-Sulfolobus system appears to exhibit host-advantage. This work provides a foundation for understanding Fusellovirus biology and virus-host coevolution in extreme ecosystems.