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


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.


HIV 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).

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)


  1. 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
  2. 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
  3. 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
  4. Bryant AK, Moore DJ, Burdo TH, Lakritz JR, Gouaux B, Soontornniyomkij V, Achim CL, Masliah E, Grant I, Levine AJ, Ellis RJ (2017) Plasma soluble CD163 is associated with postmortem brain pathology in human immunodeficiency virus infection. AIDS (London, England) 31:973–979CrossRefGoogle Scholar
  5. Burdo TH, Soulas C, Orzechowski K, Button J, Krishnan A, Sugimoto C, Alvarez X, Kuroda MJ, Williams KC (2010) Increased monocyte turnover from bone marrow correlates with severity of SIV encephalitis and CD163 levels in plasma. PLoS Pathog 6:e1000842CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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
  7. 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
  8. Burdo TH, Weiffenbach A, Woods SP, Letendre S, Ellis RJ, Williams KC (2013) Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection. AIDS (London, England) 27:1387–1395CrossRefGoogle Scholar
  9. 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
  10. Chivero ET, Guo ML, Periyasamy P, Liao K, Callen SE, Buch S (2017) HIV-1 tat primes and activates microglial NLRP3 Inflammasome-mediated neuroinflammation. J Neurosci 37:3599–3609CrossRefPubMedPubMedCentralGoogle Scholar
  11. Crowe SM, Westhorpe CLV, Mukhamedova N, Jaworowski A, Sviridov D, Bukrinsky M (2010) The macrophage: the intersection between HIV infection and atherosclerosis. J Leukoc Biol 87:589–598CrossRefPubMedPubMedCentralGoogle Scholar
  12. Currier JS, Taylor A, Boyd F, Dezii CM, Kawabata H, Burtcel B, Maa JF, Hodder S (2003) Coronary heart disease in HIV-infected individuals. J Acquir Immune Defic Syndr 33:506–512CrossRefPubMedGoogle Scholar
  13. DeLuca C, Kwon H, Lin R, Wainberg M, Hiscott J (1999) NF-kappaB activation and HIV-1 induced apoptosis. Cytokine Growth Factor Rev 10:235–253CrossRefPubMedGoogle Scholar
  14. Doitsh G, Galloway NLK, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, Greene WC (2014) Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 505:509–514CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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
  16. Fitch KV, Srinivasa S, Abbara S, Burdo TH, Williams KC, Eneh P, Lo J, Grinspoon SK (2013) Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis 208:1737–1746CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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
  18. Fourman LT, Czerwonka N, Shaikh SD, Stanley TL, Burdo TH, Williams KC, Fitch KV, Lo J, Grinspoon SK (2018) Insulin-like growth factor 1 inversely relates to monocyte/macrophage activation markers in HIV. AIDS 32(7):927–932PubMedGoogle Scholar
  19. Group (2015) I.S.S., et al. initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med 373:795–807CrossRefGoogle Scholar
  20. Guo H, Gao J, Taxman DJ, Ting JP, Su L (2014) HIV-1 infection induces interleukin-1beta production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes. J Biol Chem 289:21716–21726CrossRefPubMedPubMedCentralGoogle Scholar
  21. Guo H, Callaway JB, Ting JP (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21:677–687CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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
  23. Hernandez JC, Latz E, Urcuqui-Inchima S (2014) HIV-1 induces the first signal to activate the NLRP3 inflammasome in monocyte-derived macrophages. Intervirology 57:36–42CrossRefPubMedGoogle Scholar
  24. Hoseini Z, Sepahvand F, Rashidi B, Sahebkar A, Masoudifar A, Mirzaei H (2018) NLRP3 inflammasome: its regulation and involvement in atherosclerosis. J Cell Physiol 233:2116–2132CrossRefPubMedGoogle Scholar
  25. Kearns A, Gordon J, Burdo TH, Qin X (2017a) HIV-1-associated atherosclerosis: unraveling the missing link. J Am Coll Cardiol 69:3084–3098CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kearns A, Burdo TH, Qin X (2017b) Editorial commentary: clinical management of cardiovascular disease in HIV-infected patients. Trends Cardiovasc Med 27:564–566CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kelesidis T, Kendall MA, Yang OO, Hodis HN, Currier JS (2012) Biomarkers of microbial translocation and macrophage activation: association with progression of subclinical atherosclerosis in HIV-1 infection. J Infect Dis 206:1558–1567CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kudo S, Mizuno K, Hirai Y, Shimizu T (1990) Clearance and tissue distribution of recombinant human interleukin 1 beta in rats. Cancer Res 50:5751–5755PubMedGoogle Scholar
  29. Lakritz JR, Robinson JA, Polydefkis MJ, Miller AD, Burdo TH (2015a) Loss of intraepidermal nerve fiber density during SIV peripheral neuropathy is mediated by monocyte activation and elevated monocyte chemotactic proteins. J Neuroinflammation 12:237CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lakritz JR, Bodair A, Shah N, O'Donnell R, Polydefkis MJ, Miller AD, Burdo TH (2015b) Monocyte traffic, dorsal root ganglion histopathology, and loss of Intraepidermal nerve Fiber density in SIV peripheral neuropathy. Am J Pathol 185:1912–1923CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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
  32. Liu X et al (2014) HIV-1 Nef induces CCL5 production in astrocytes through p38-MAPK and PI3K/Akt pathway and utilizes NF-kB, CEBP and AP-1 transcription factors. Sci Rep 4:4450CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lohse N, Hansen ABE, Pedersen G, Kronborg G, Gerstoft J, Sørensen HT, Væth M, Obel N (2007) Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med 146:87–95CrossRefPubMedGoogle Scholar
  34. Mamik MK et al (2017) HIV-1 viral protein R activates NLRP3 Inflammasome in microglia: implications for HIV-1 associated Neuroinflammation. J Neuroimmune Pharmacol 12:233–248CrossRefPubMedGoogle Scholar
  35. Mayne M, Bratanich AC, Chen P, Rana F, Nath A, Power C (1998) HIV-1 tat molecular diversity and induction of TNF-alpha: implications for HIV-induced neurological disease. Neuroimmunomodulation 5:184–192CrossRefPubMedGoogle Scholar
  36. 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
  37. Pereyra F, Lo J, Triant VA, Wei J, Buzon MJ, Fitch KV, Hwang J, Campbell JH, Burdo TH, Williams KC, Abbara S, Grinspoon SK (2012) Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers. AIDS (London, England) 26:2409–2412CrossRefGoogle Scholar
  38. 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
  39. Royal W 3rd et al (2016) Associations between cognition, gender and monocyte activation among HIV infected individuals in Nigeria. PLoS One 11:e0147182CrossRefPubMedPubMedCentralGoogle Scholar
  40. 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
  41. Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M, Mankowski JL, Brown A, Volsky DJ, McArthur JC (2016) HIV-associated neurocognitive disorder - pathogenesis and prospects for treatment. Nat Rev Neurol 12:309CrossRefPubMedPubMedCentralGoogle Scholar
  42. 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
  43. Shamaa OR, Mitra S, Gavrilin MA, Wewers MD (2015) Monocyte Caspase-1 is released in a stable, active high molecular weight complex distinct from the unstable cell lysate-activated Caspase-1. PLoS One 10:e0142203CrossRefPubMedPubMedCentralGoogle Scholar
  44. Shive CL, Jiang W, Anthony DD, Lederman MM (2015) Soluble CD14 is a nonspecific marker of monocyte activation. AIDS (London, England) 29:1263–1265CrossRefGoogle Scholar
  45. Siedner MJ (2016) START or SMART? Timing of antiretroviral therapy initiation and cardiovascular risk for people with human immunodeficiency virus infection. Open Forum Infect Dis 3:ofw032CrossRefPubMedPubMedCentralGoogle Scholar
  46. 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
  47. Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, Corsini E, Abdelbaky A, Zanni MV, Hoffmann U, Williams KC, Lo J, Grinspoon SK (2012) Arterial inflammation in patients with HIV. JAMA 308:379–386CrossRefPubMedPubMedCentralGoogle Scholar
  48. 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
  49. 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
  50. Triant VA, Lee H, Hadigan C, Grinspoon SK (2007) Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab 92:2506–2512CrossRefPubMedPubMedCentralGoogle Scholar
  51. Varin A, Manna SK, Quivy V, Decrion AZ, van Lint C, Herbein G, Aggarwal BB (2003) Exogenous Nef protein activates NF-kappa B, AP-1, and c-Jun N-terminal kinase and stimulates HIV transcription in promonocytic cells. Role in AIDS pathogenesis. J Biol Chem 278:2219–2227CrossRefPubMedGoogle Scholar
  52. Walker JA, Sulciner ML, Nowicki KD, Miller AD, Burdo TH, Williams KC (2014) Elevated numbers of CD163+ macrophages in hearts of simian immunodeficiency virus-infected monkeys correlate with cardiac pathology and fibrosis. AIDS Res Hum Retrovir 30:685–694CrossRefPubMedGoogle Scholar
  53. Walsh JG, Reinke SN, Mamik MK, McKenzie BA, Maingat F, Branton WG, Broadhurst DI, Power C (2014) Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS. Retrovirology 11:35CrossRefPubMedPubMedCentralGoogle Scholar
  54. 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
  55. Yearley JH, Xia D, Pearson CB, Carville A, Shannon RP, Mansfield KG (2009) Interleukin-18 predicts atherosclerosis progression in SIV-infected and uninfected rhesus monkeys (Macaca mulatta) on a high-fat/high-cholesterol diet. Lab Investig 89:657–667CrossRefPubMedGoogle Scholar
  56. 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 1:474–480CrossRefPubMedPubMedCentralGoogle Scholar

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

Personalised recommendations