Caspase-1-associated immune activation in an accelerated SIV-infected rhesus macaque model
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.
KeywordsHIV Caspase-1 Inflammation HIV-associated comorbidities SIV
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).
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).
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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.
- Ahmad F, Mishra N, Ahrenstof G, Franklin BS, Latz E, Schmidt RE, Bossaller L (2017) Evidence of inflammasome activation and formation of monocyte derived ASC-specks in HIV-1 positive patients. AIDS 32:299–307Google Scholar
- Alcaide ML, Parmigiani A, Pallikkuth S, Roach M, Freguja R, Negra MD, Bolivar H, Fischl MA, Pahwa S (2013) Immune activation in HIV-infected aging women on antiretrovirals--implications for age-associated comorbidities: a cross-sectional pilot study. PLoS One 8:e63804CrossRefPubMedPubMedCentralGoogle Scholar
- Barouch DH, Ghneim K, Bosche WJ, Li Y, Berkemeier B, Hull M, Bhattacharyya S, Cameron M, Liu J, Smith K, Borducchi E, Cabral C, Peter L, Brinkman A, Shetty M, Li H, Gittens C, Baker C, Wagner W, Lewis MG, Colantonio A, Kang HJ, Li W, Lifson JD, Piatak M Jr, Sekaly RP (2016) Rapid Inflammasome activation following mucosal SIV infection of rhesus monkeys. Cell 165:656–667CrossRefPubMedPubMedCentralGoogle Scholar
- Burdo TH, Lentz MR, Autissier P, Krishnan A, Halpern E, Letendre S, Rosenberg ES, Ellis RJ, Williams KC (2011a) Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after anti-retroviral therapy. J Infect Dis 204:154–163CrossRefPubMedPubMedCentralGoogle Scholar
- Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, Rosenberg ES, Williams KC, Grinspoon S (2011b) Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J Infect Dis 204:1227–1236CrossRefPubMedPubMedCentralGoogle Scholar
- Chattergoon MA, Latanich R, Quinn J, Winter ME, Buckheit RW, Blankson JN, Pardoll D, Cox AL (2014) HIV and HCV activate the inflammasome in monocytes and macrophages via endosomal toll-like receptors without induction of type 1 interferon. PLoS Pathog 10:e1004082CrossRefPubMedPubMedCentralGoogle Scholar
- Effros RB, Fletcher CV, Gebo K, Halter JB, Hazzard WR, Horne FMF, Huebner RE, Janoff EN, Justice AC, Kuritzkes D, Nayfield SG, Plaeger SF, Schmader KE, Ashworth JR, Campanelli C, Clayton CP, Rada B, Woolard NF, High KP (2008) Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis 47:542–553CrossRefPubMedPubMedCentralGoogle Scholar
- Fiume G, Vecchio E, de Laurentiis A, Trimboli F, Palmieri C, Pisano A, Falcone C, Pontoriero M, Rossi A, Scialdone A, Fasanella Masci F, Scala G, Quinto I (2012) Human immunodeficiency virus-1 Tat activates NF-kappaB via physical interaction with IkappaB-alpha and p65. Nucleic Acids Res 40:3548–3562CrossRefPubMedGoogle Scholar
- Hasegawa A, Liu H, Ling B, Borda JT, Alvarez X, Sugimoto C, Vinet-Oliphant H, Kim WK, Williams KC, Ribeiro RM, Lackner AA, Veazey RS, Kuroda MJ (2009) The level of monocyte turnover predicts disease progression in the macaque model of AIDS. Blood 114:2917–2925CrossRefPubMedPubMedCentralGoogle Scholar
- Lederer S, Favre D, Walters KA, Proll S, Kanwar B, Kasakow Z, Baskin CR, Palermo R, McCune JM, Katze MG (2009) Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization. PLoS Pathog 5:e1000296CrossRefPubMedPubMedCentralGoogle Scholar
- Olivetta E, Percario Z, Fiorucci G, Mattia G, Schiavoni I, Dennis C, Jager J, Harris M, Romeo G, Affabris E, Federico M (2003) HIV-1 Nef induces the release of inflammatory factors from human monocyte/macrophages: involvement of Nef endocytotic signals and NF-kappa B activation. J Immunol 170:1716–1727CrossRefPubMedGoogle Scholar
- Porcheray F, Samah B, Leone C, Dereuddre-Bosquet N, Gras G (2006) Macrophage activation and human immunodeficiency virus infection: HIV replication directs macrophages towards a pro-inflammatory phenotype while previous activation modulates macrophage susceptibility to infection and viral production. Virology 349:112–120CrossRefPubMedGoogle Scholar
- Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, Pedersen C, Ruxrungtham K, Lewin SR, Emery S, Neaton JD, Brenchley JM, Deeks SG, Sereti I, Douek DC, INSIGHT SMART Study Group (2011) Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 203:780–790CrossRefPubMedPubMedCentralGoogle Scholar
- Shah A, Verma AS, Patel KH, Noel R, Rivera-Amill V, Silverstein PS, Chaudhary S, Bhat HK, Stamatatos L, Singh DP, Buch S, Kumar A (2011) HIV-1 gp120 induces expression of IL-6 through a nuclear factor-kappa B-dependent mechanism: suppression by gp120 specific small interfering RNA. PLoS One 6:e21261CrossRefPubMedPubMedCentralGoogle Scholar
- Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, Kowalska JD, de Wit S, Law M, el Sadr W, Kirk O, Friis-Moller N, Monforte A'A, Phillips AN, Sabin CA, Lundgren JD (2014) Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet 384:241–248CrossRefPubMedGoogle Scholar
- Tawakol A, Ishai A, Li D, Takx RA, Hur S, Kaiser Y, Pampaloni M, Rupert A, Hsu D, Sereti I, Fromentin R, Chomont N, Ganz P, Deeks SG, Hsue PY (2017) Association of arterial and lymph node inflammation with distinct inflammatory pathways in human immunodeficiency virus infection. JAMA Cardiol 2(2):163–171CrossRefPubMedPubMedCentralGoogle Scholar
- Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B, Hunt PW, Plants J, Seth A, Wilson CC, Deeks SG, Lederman MM, Landay AL (2014) Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis 210:1248–1259CrossRefPubMedPubMedCentralGoogle Scholar
- Williams K, Burdo TH (2012) Monocyte mobilization, activation markers, and unique macrophage populations in the brain: observations from SIV infected monkeys are informative with regard to pathogenic mechanisms of HIV infection in humans. J NeuroImmune Pharmacol 7:363–371CrossRefPubMedGoogle Scholar
- Zanni MV, Toribio M, Robbins GK, Burdo TH, Lu MT, Ishai AE, Feldpausch MN, Martin A, Melbourne K, Triant VA, Suchindran S, Lee H, Hoffmann U, Williams KC, Tawakol A, Grinspoon SK (2016) Effects of antiretroviral therapy on immune function and arterial inflammation in treatment-naive patients with human immunodeficiency virus infection. JAMA Cardiol 1:474–480CrossRefPubMedGoogle Scholar