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Journal of NeuroVirology

, Volume 24, Issue 4, pp 420–431 | Cite as

Caspase-1-associated immune activation in an accelerated SIV-infected rhesus macaque model

  • Alison C. Kearns
  • Jake A. Robinson
  • Masoud Shekarabi
  • Fengming Liu
  • Xuebin Qin
  • Tricia H. Burdo
Article

Abstract

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-1β) 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-1β, 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-κB 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.

Keywords

HIV Caspase-1 Inflammation HIV-associated comorbidities SIV 

Notes

Acknowledgements

This work was supported by NIH grants R01 NS082116 (THB), R01CA166144 (XQ), R01 HL130233 (XQ), and R21 AA024984 (XQ), as well as W.W. Smith Charitable Trust A1502 (XQ). The in vivo CD8-depletion antibodies used in these studies were purchased from the NIH Nonhuman Primate Reagent Resource under grants RR016001 and AI040101. We thank Merck and Gilead for the ART drugs used in this study. We would like to thank veterinary staff at the Tulane National Primate Research Center for animal care, and pathology residents and staff for assisting with necropsies and tissue collection and Dr. Xavier Alvarez and research technician Cecily Midkiff for their assistance on this project. We would like to acknowledge the Tulane National Primate Research Center Tulane’s base grant for SIV− tissues and SIVmac251 viral stocks (P51OD011104).

Author contributions

Principal contributions of the authors are project conception/design (THB, XQ), data acquisition and analysis (AK, JAR, MS, FL), statistical analysis and interpretation (AK, JAR, XQ, THB), drafting of the manuscript (AK, JAR, XQ, THB), and critical revision of the manuscript (AK, JAR, XQ, MS, FL, THB).

Compliance with ethical standards

Conflicts of interests

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Supplementary material

13365_2018_630_MOESM1_ESM.docx (1016 kb)
ESM 1 (DOCX 1015 kb)

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Copyright information

© Journal of NeuroVirology, Inc. 2018

Authors and Affiliations

  • Alison C. Kearns
    • 1
  • Jake A. Robinson
    • 1
  • Masoud Shekarabi
    • 1
  • Fengming Liu
    • 1
  • Xuebin Qin
    • 1
  • Tricia H. Burdo
    • 1
  1. 1.Department of Neuroscience, Lewis Katz School of MedicineTemple UniversityPhiladelphiaUSA

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