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

Genomics Genomics
Immunology Immunology
Infectious Disease Infectious Disease
Alex K. Shalek Alex K. Shalek
Ira Fleming Ira Fleming
Jennyfer Galvez-Reyes Jennyfer Galvez-Reyes
Sam Kazer Sam Kazer
Vincent Miao Vincent Miao

Wilk et al.▾ Wilk, A.J., Marceau, J.O., Kazer, S.W., Fleming, I., Miao, V., Galvez-Reyes, J., Shalek, A.K., Holmes, S., Overbaugh, J., Blish, C.A.


March, 2023


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.