Qualitative differences in the innate and adaptive responses elicited by different HIV vaccine candidates have not been thoroughly investigated. We tested the ability of the Aventis Pasteur live recombinant canarypox vector (ALVAC)–SIV, DNA–SIV and Ad26–SIV vaccine prime modalities together with two ALVAC–SIV + gp120 protein boosts to reduce the risk of SIVmac251 acquisition in rhesus macaques. We found that the DNA and ALVAC prime regimens were effective, but the Ad26 prime was not. The activation of hypoxia and the inflammasome in CD14+CD16− monocytes, gut-homing CCR5-negative CD4+ T helper 2 (TH2) cells and antibodies to variable region 2 correlated with a decreased risk of SIVmac251 acquisition. By contrast, signal transducer and activator of transcription 3 activation in CD16+ monocytes was associated with an increased risk of virus acquisition. The Ad26 prime regimen induced the accumulation of CX3CR1+CD163+ macrophages in lymph nodes and of long-lasting CD4+ TH17 cells in the gut and lungs. Our data indicate that the selective engagement of monocyte subsets following a vaccine prime influences long-term immunity, uncovering an unexpected association of CD14+ innate monocytes with a reduced risk of SIVmac251 acquisition.
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Pitisuttithum, P. et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J. Infect. Dis. 194, 1661–1671 (2006).
Gray, G. E. et al. Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study. Lancet Infect. Dis. 11, 507–515 (2011).
Buchbinder, S. P. et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 1881–1893 (2008).
Hammer, S. M. et al. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N. Engl. J. Med. 369, 2083–2092 (2013).
Rerks-Ngarm, S. et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 361, 2209–2220 (2009).
Haynes, B. F. et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N. Engl. J. Med. 366, 1275–1286 (2012).
Zolla-Pazner, S. et al. Vaccine-induced IgG antibodies to V1V2 regions of multiple HIV-1 subtypes correlate with decreased risk of HIV-1 infection. PLoS ONE 9, e87572 (2014).
Lin, L. et al. COMPASS identifies T-cell subsets correlated with clinical outcomes. Nat. Biotechnol. 33, 610–616 (2015).
Tomaras, G. D. et al. Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG. Proc. Natl Acad. Sci. USA 110, 9019–9024 (2013).
Vaccari, M. et al. Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. Nat. Med. 22, 762–770 (2016).
Vaccari, M. et al. Reduced protection from simian immunodeficiency virus SIVmac251 infection afforded by memory CD8+ T cells induced by vaccination during CD4+ T-cell deficiency. J. Virol. 82, 9629–9638 (2008).
Baden, L. R. et al. Induction of HIV-1-specific mucosal immune responses following intramuscular recombinant adenovirus serotype 26 HIV-1 vaccination of humans. J. Infect. Dis. 211, 518–528 (2015).
Shi, L. Z. et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).
Winning, S. & Fandrey, J. Dendritic cells under hypoxia: how oxygen shortage affects the linkage between innate and adaptive immunity. J. Immunol. Res. 2016, 5134329 (2016).
Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002).
Strbo, N. et al. Cutting edge: novel vaccination modality provides significant protection against mucosal infection by highly pathogenic simian immunodeficiency virus. J. Immunol. 190, 2495–2499 (2013).
Pegu, P. et al. Antibodies with high avidity to the gp120 envelope protein in protection from simian immunodeficiency virus SIVmac251 acquisition in an immunization regimen that mimics the RV-144 Thai trial. J. Virol. 87, 1708–1719 (2013).
Shi, C. & Pamer, E. G. Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11, 762–774 (2011).
Carr, M. W. et al. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc. Natl Acad. Sci. USA 91, 3652–3656 (1994).
Yago, T. et al. IL-23 and Th17 disease in inflammatory arthritis. J. Clin. Med. 6, 81 (2017).
Chong, S. Z. et al. CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses. J. Exp. Med. 213, 2293–2314 (2016).
Bao, W. et al. Sodium salicylate modulates inflammatory responses through AMP-activated protein kinase activation in LPS-stimulated THP-1 cells. J. Cell. Biochem. 119, 850-860 (2018).
Chung, Y. H., Kim, D. H. & Lee, W. W. Monosodium urate crystal-induced pro-interleukin-1β production is post-transcriptionally regulated via the p38 signaling pathway in human monocytes. Sci. Rep. 6, 34533 (2016).
Fan, S. et al. The eIF4E/eIF4G interaction inhibitor 4EGI-1 augments TRAIL-mediated apoptosis through c-FLIP down-regulation and DR5 induction independent of inhibition of cap-dependent protein translation. Neoplasia 12, 346–356 (2010).
Kung, C. P. & Raab-Traub, N. Epstein–Barr virus latent membrane protein 1 induces expression of the epidermal growth factor receptor through effects on Bcl-3 and STAT3. J. Virol. 82, 5486–5493 (2008).
Kwissa, M. et al. Dengue virus infection induces expansion of a CD14+CD16+ monocyte population that stimulates plasmablast differentiation. Cell Host Microbe 16, 115–127 (2014).
Ludtke, A. et al. Ebola virus disease is characterized by poor activation and reduced levels of circulating CD16+ monocytes. J. Infect. Dis. 214, S275–S280 (2016).
Yu, Q. et al. Comparative analysis of tropism between canarypox (ALVAC) and vaccinia viruses reveals a more restricted and preferential tropism of ALVAC for human cells of the monocytic lineage. Vaccine 24, 6376–6391 (2006).
Ignatius, R. et al. Canarypox virus–induced maturation of dendritic cells is mediated by apoptotic cell death and tumor necrosis factor alpha secretion. J. Virol. 74, 11329–11338 (2000).
Fernandes-Alnemri, T. et al. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509–513 (2009).
Muruve, D. A. et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452, 103–107 (2008).
Rao, S. P. et al. Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis. PLoS ONE 7, e39416 (2012).
Rivino, L. et al. Chemokine receptor expression identifies pre-T helper (Th)1, pre-Th2, and nonpolarized cells among human CD4+ central memory T cells. J. Exp. Med. 200, 725–735 (2004).
Auclair, S. L. et al. Distinct susceptibility of HIV vaccine vector-induced CD4 T cells to HIV infection. PLoS Pathog. 14, e1006888 (2018).
Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009).
Rossol, M. et al. The CD14brightCD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population. Arthritis Rheum. 64, 671–677 (2012).
Zhu, H. et al. CD16+ monocyte subset was enriched and functionally exacerbated in driving T-cell activation and B-cell response in systemic lupus erythematosus. Front. Immunol. 7, 512 (2016).
Eisenbarth, S. C. et al. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008).
Liu, F. et al. Priming and activation of inflammasome by canarypox virus vector ALVAC via the cGAS/IFI16–STING–type I IFN pathway and AIM2 sensor. J. Immunol. 199, 3293–3305 (2017).
Suschak, J. J. et al. Identification of Aim2 as a sensor for DNA vaccines. J. Immunol. 194, 630–636 (2015).
Teigler, J. E., Iampietro, M. J. & Barouch, D. H. Vaccination with adenovirus serotypes 35, 26, and 48 elicits higher levels of innate cytokine responses than adenovirus serotype 5 in rhesus monkeys. J. Virol. 86, 9590–9598 (2012).
Teigler, J. E. et al. The canarypox virus vector ALVAC induces distinct cytokine responses compared to the vaccinia virus-based vectors MVA and NYVAC in rhesus monkeys. J. Virol. 88, 1809–1814 (2014).
Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161.e12 (2018).
Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).
Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).
Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).
Ghonime, M. G. et al. Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J. Immunol. 192, 3881–3888 (2014).
Panchanathan, R., Liu, H. & Choubey, D. Hypoxia primes human normal prostate epithelial cells and cancer cell lines for the NLRP3 and AIM2 inflammasome activation. Oncotarget 7, 28183–28194 (2016).
Gu, L. et al. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 404, 407–411 (2000).
Cecchinato, V. et al. Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal Immunol. 1, 279–288 (2008).
Fouts, T. R. et al. Balance of cellular and humoral immunity determines the level of protection by HIV vaccines in rhesus macaque models of HIV infection. Proc. Natl Acad. Sci. USA 112, E992–E999 (2015).
Qureshi, H. et al. Low-dose penile SIVmac251 exposure of rhesus macaques infected with adenovirus type 5 (Ad5) and then immunized with a replication-defective Ad5-based SIV gag/pol/nef vaccine recapitulates the results of the phase IIb step trial of a similar HIV-1 vaccine. J. Virol. 86, 2239–2250 (2012).
Reinhardt-Heller, K. et al. Increase of intermediate monocytes in graft-versus-host disease: correlation with MDR1+ Th17.1 levels and the effect of prednisolone and 1α,25-dihydroxyvitamin D3. Biol. Blood Marrow Transplant. 23, 2057–2064 (2017).
Joubert, P. E. et al. Autophagy induction by the pathogen receptor CD46. Cell Host Microbe 6, 354–366 (2009).
Rodriguez-Rocha, H. et al. Adenoviruses induce autophagy to promote virus replication and oncolysis. Virology 416, 9–15 (2011).
Shi, C. S. et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255–263 (2012).
Byrne, B. G. et al. Inflammasome components coordinate autophagy and pyroptosis as macrophage responses to infection. mBio 4, e00620-12 (2013).
Barouch, D. H. et al. Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature 482, 89–93 (2012).
Strickland, S. L. et al. Significant genetic heterogeneity of the SIVmac251 viral swarm derived from different sources. AIDS Res. Hum. Retroviruses 27, 1327–1332 (2011).
Stott, E. J. Anti-cell antibody in macaques. Nature 353, 393 (1991).
Barouch, D. H. et al. Characterization of humoral and cellular immune responses elicited by a recombinant adenovirus serotype 26 HIV-1 Env vaccine in healthy adults (IPCAVD 001). J. Infect. Dis. 207, 248–256 (2013).
Rosati, M. et al. Increased immune responses in rhesus macaques by DNA vaccination combined with electroporation. Vaccine 26, 5223–5229 (2008).
Keele, B. F. et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl Acad. Sci. USA 105, 7552–7557 (2008).
Keele, B. F. et al. Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1. J. Exp. Med. 206, 1117–1134 (2009).
Romano, J. W. et al. NASBA technology: isothermal RNA amplification in qualitative and quantitative diagnostics. Immunol. Invest. 26, 15–28 (1997).
Vaccari, M. et al. Vaccine-induced CD8+ central memory T cells in protection from simian AIDS. J. Immunol. 175, 3502–3507 (2005).
Schiffner, T. et al. Immune focusing and enhanced neutralization induced by HIV-1 gp140 chemical cross-linking. J. Virol. 87, 10163–10172 (2013).
Li, M. et al. Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J. Virol. 79, 10108–10125 (2005).
Autissier, P., Soulas, C., Burdo, T. H. & Williams, K. C. Immunophenotyping of lymphocyte, monocyte and dendritic cell subsets in normal rhesus macaques by 12-color flow cytometry: clarification on DC heterogeneity. J. Immunol. Methods 360, 119–128 (2010).
Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
Nakaya, H. I. et al. Systems biology of vaccination for seasonal influenza in humans. Nat. Immunol. 12, 786–795 (2011).
Gundem, G. & Lopez-Bigas, N. Sample-level enrichment analysis unravels shared stress phenotypes among multiple cancer types. Genome Med. 4, 28 (2012).
Montojo, J. et al. GeneMANIA Cytoscape plugin: fast gene function predictions on the desktop. Bioinformatics 26, 2927–2928 (2010).
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).
We thank D. Ahern for editorial and graphical support and all of the staff at Advanced BioScience Laboratories for helping with the execution of the animal study. We thank J. Lucas, J. Peel and Y. Lin for specific binding and total antibody assays and G. Overman and N. Yates for assay and technical assistance. We thank D. Barouch (Harvard Medical School) for providing the Ad26–SIV recombinant vaccine. This work was mostly supported with federal funds from the intramural program of the National Cancer Institute, NIH, including contract no. HHSN261200800001E (G.F.). Contributions were made by the extramural NIAID program (HHSN27201100016C; D.M.), the Henry M. Jackson Foundation, the US Department of Defense and the Collaboration for Aids Vaccine Discovery (CAVD) grants OPP1032325 (R.A.K.) and OPP1147555 (R.A.K.) from the Bill and Melinda Gates Foundation. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.
The US Government in conjunction with Sanofi Pasteur holds Patent 5766598: A Recombinant Attenuated ALVAC Canarypox virus Expression Vectors Containing Heterologous DNA Segments Encoding Lentiviral Gene, inventors E. Paoletti, J. Tartaglia and W. I. Cox, issued 16 June 1998, for the ALVAC vaccine. The US Government also holds Patent 7094408: Improved Immunogenicity Using a Combination of DNA and Vaccinia Virus Vector Vaccines, inventors G. Franchini, Z. Hel and G. Pavlakis, issued 22 August 2006. This patent is for the combination DNA and ALVAC poxvirus vaccines.
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Vaccari, M., Fourati, S., Gordon, S.N. et al. HIV vaccine candidate activation of hypoxia and the inflammasome in CD14+ monocytes is associated with a decreased risk of SIVmac251 acquisition. Nat Med 24, 847–856 (2018). https://doi.org/10.1038/s41591-018-0025-7
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