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Kearns AC , Robinson JA , Shekarabi M , Liu F , Qin X , Burdo TH
Caspase-1-associated immune activation in an accelerated SIV-infected rhesus macaque model
J Neurovirol. 2018 Aug;24(4) :420-431
PMID: 29611111    PMCID: PMC6526524    URL: https://www.ncbi.nlm.nih.gov/pubmed/29611111
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In the antiretroviral therapy (ART) era, chronic HIV infection is primarily associated with chronic inflammation driving comorbidities such as cardiovascular disease and neurocognitive impairment. Caspase-1 activation in leukocytes has been documented in HIV infection; however, whether caspase-1 activation and the downstream pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin-18 (IL-18) contribute to chronic inflammation in HIV comorbidities remains undetermined. The relationship between the caspase-1 cascade and persistent inflammation in HIV has not been investigated. Here, we used an accelerated simian immunodeficiency virus (SIV)-infected rhesus macaque model with or without ART to investigate the dynamics of caspase-1 and immune cell activation before infection, 21 days post infection (dpi), and necropsy. Caspase-1, IL-18, IL-1beta, and immune markers were measured both in the circulation and lymphoid tissues. We found a significant increase in caspase-1 and IL-18 in SIV infection that positively correlated with inflammatory monocytes and negatively correlated with CD4(+) T cell counts. ART attenuated these effects at necropsy in the circulation. Further, lymph nodes from SIV+ or SIV+ART animals had increased activation of caspase-1 and potential upstream priming of the NF-kappaB pathway, indicating that tissue-specific immune activation persists with ART. Together, these results shed light on the interconnectedness of the caspase-1 pathway and peripheral immune activation and further indicate that ART is not sufficient for suppressing inflammation. The caspase-1 pathway may provide novel therapeutic targets to improve HIV-associated comorbidities and health outcomes in the context of viral suppression.
1538-2443 Kearns, Alison C Robinson, Jake A Shekarabi, Masoud Liu, Fengming Qin, Xuebin Burdo, Tricia H NS082116/National Institute of Neurological Disorders and Stroke CA166144/National Cancer Institute HL130233/National Heart, Lung, and Blood Institute AA024984/National Institute on Alcohol Abuse and Alcoholism Journal Article United States J Neurovirol. 2018 Apr 2. pii: 10.1007/s13365-018-0630-8. doi: 10.1007/s13365-018-0630-8.