HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy.
Adult
Anti-Retroviral Agents
/ administration & dosage
CD4-Positive T-Lymphocytes
/ virology
Disease Reservoirs
/ virology
Female
HIV Infections
/ drug therapy
HIV-1
/ drug effects
Humans
Macrophages
/ virology
Male
Middle Aged
RNA, Viral
/ genetics
Urethra
/ virology
Virus Replication
/ drug effects
Journal
Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
04
07
2018
accepted:
04
12
2018
pubmed:
6
2
2019
medline:
30
7
2019
entrez:
6
2
2019
Statut:
ppublish
Résumé
Human immunodeficiency virus type 1 (HIV-1) eradication is prevented by the establishment on infection of cellular HIV-1 reservoirs that are not fully characterized, especially in genital mucosal tissues (the main HIV-1 entry portal on sexual transmission). Here, we show, using penile tissues from HIV-1-infected individuals under suppressive combination antiretroviral therapy, that urethral macrophages contain integrated HIV-1 DNA, RNA, proteins and intact virions in virus-containing compartment-like structures, whereas viral components remain undetectable in urethral T cells. Moreover, urethral cells specifically release replication-competent infectious HIV-1 following reactivation with the macrophage activator lipopolysaccharide, while the T-cell activator phytohaemagglutinin is ineffective. HIV-1 urethral reservoirs localize preferentially in a subset of polarized macrophages that highly expresses the interleukin-1 receptor, CD206 and interleukin-4 receptor, but not CD163. To our knowledge, these results are the first evidence that human urethral tissue macrophages constitute a principal HIV-1 reservoir. Such findings are determinant for therapeutic strategies aimed at HIV-1 eradication.
Identifiants
pubmed: 30718846
doi: 10.1038/s41564-018-0335-z
pii: 10.1038/s41564-018-0335-z
doi:
Substances chimiques
Anti-Retroviral Agents
0
RNA, Viral
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
633-644Commentaires et corrections
Type : CommentIn
Type : CommentIn
Références
Sengupta, S. & Siliciano, R. F. Targeting the latent reservoir for HIV-1. Immunity 48, 872–895 (2018).
doi: 10.1016/j.immuni.2018.04.030
Gaudin, R. et al. Dynamics of HIV-containing compartments in macrophages reveal sequestration of virions and transient surface connections. PLoS ONE 8, e69450 (2013).
doi: 10.1371/journal.pone.0069450
Castellano, P., Prevedel, L. & Eugenin, E. A. HIV-infected macrophages and microglia that survive acute infection become viral reservoirs by a mechanism involving Bim. Sci. Rep. 7, 12866 (2017).
doi: 10.1038/s41598-017-12758-w
Swingler, S., Mann, A. M., Zhou, J., Swingler, C. & Stevenson, M. Apoptotic killing of HIV-1-infected macrophages is subverted by the viral envelope glycoprotein. PLoS Pathog. 3, 1281–1290 (2007).
doi: 10.1371/journal.ppat.0030134
Clayton, K. L. et al. Resistance of HIV-infected macrophages to CD8
doi: 10.1038/s41590-018-0085-3
Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).
doi: 10.1016/j.immuni.2013.04.004
Murray, P. J. & Wynn, T. A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723–737 (2011).
doi: 10.1038/nri3073
Murray, P. J. Macrophage polarization. Annu. Rev. Physiol. 79, 541–566 (2017).
doi: 10.1146/annurev-physiol-022516-034339
Cassol, E., Cassetta, L., Alfano, M. & Poli, G. Macrophage polarization and HIV-1 infection. J. Leukoc. Biol. 87, 599–608 (2010).
doi: 10.1189/jlb.1009673
Bailey, J. R. et al. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4
doi: 10.1128/JVI.00591-06
Perelson, A. S. et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387, 188–191 (1997).
doi: 10.1038/387188a0
Rasmussen, T. A. et al. Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Hum. Vaccin. Immunother. 9, 993–1001 (2013).
doi: 10.4161/hv.23800
Honeycutt, J. B. et al. Macrophages sustain HIV replication in vivo independently of T cells. J. Clin. Invest. 126, 1353–1366 (2016).
doi: 10.1172/JCI84456
Honeycutt, J. B. et al. HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy. Nat. Med. 23, 638–643 (2017).
doi: 10.1038/nm.4319
Sullivan, P. S., Salazar, L., Buchbinder, S. & Sanchez, T. H. Estimating the proportion of HIV transmissions from main sex partners among men who have sex with men in five US cities. AIDS 23, 1153–1162 (2009).
doi: 10.1097/QAD.0b013e32832baa34
Ganor, Y. et al. The adult penile urethra is a novel entry site for HIV-1 that preferentially targets resident urethral macrophages. Mucosal Immunol. 6, 776–786 (2013).
doi: 10.1038/mi.2012.116
Ganor, Y. et al. Within 1 h, HIV-1 uses viral synapses to enter efficiently the inner, but not outer, foreskin mucosa and engages Langerhans–T cell conjugates. Mucosal Immunol. 3, 506–522 (2010).
doi: 10.1038/mi.2010.32
Zhou, Z. et al. HIV-1 efficient entry in inner foreskin is mediated by elevated CCL5/RANTES that recruits T cells and fuels conjugate formation with Langerhans cells. PLoS Pathog. 7, e1002100 (2011).
doi: 10.1371/journal.ppat.1002100
Jensen, M. A. et al. Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences. J. Virol. 77, 13376–13388 (2003).
doi: 10.1128/JVI.77.24.13376-13388.2003
Sasaki, Y., Ohsawa, K., Kanazawa, H., Kohsaka, S. & Imai, Y. Iba1 is an actin-cross-linking protein in macrophages/microglia. Biochem. Biophys. Res. Commun. 286, 292–297 (2001).
doi: 10.1006/bbrc.2001.5388
Prevedel, L. et al. Identification, localization, and quantification of HIV reservoirs using microscopy. Curr. Protoc. Cell Biol. https://doi.org/10.1002/cpcb.64 (2018).
doi: 10.1002/cpcb.64
pubmed: 30265439
Laird, G. M., Rosenbloom, D. I., Lai, J., Siliciano, R. F. & Siliciano, J. D. Measuring the frequency of latent HIV-1 in resting CD4
doi: 10.1007/978-1-4939-3046-3_16
Fun, A., Mok, H. P., Wills, M. R. & Lever, A. M. A highly reproducible quantitative viral outgrowth assay for the measurement of the replication-competent latent HIV-1 reservoir. Sci. Rep. 7, 43231 (2017).
doi: 10.1038/srep43231
Sanyal, A. et al. Novel assay reveals a large, inducible, replication-competent HIV-1 reservoir in resting CD4
doi: 10.1038/nm.4347
Cassol, E., Cassetta, L., Rizzi, C., Alfano, M. & Poli, G. M1 and M2a polarization of human monocyte-derived macrophages inhibits HIV-1 replication by distinct mechanisms. J. Immunol. 182, 6237–6246 (2009).
doi: 10.4049/jimmunol.0803447
Sharova, N., Swingler, C., Sharkey, M. & Stevenson, M. Macrophages archive HIV-1 virions for dissemination in trans. EMBO J. 24, 2481–2489 (2005).
doi: 10.1038/sj.emboj.7600707
Zanin-Zhorov, A. et al. Cutting edge: T cells respond to lipopolysaccharide innately via TLR4 signaling. J. Immunol. 179, 41–44 (2007).
doi: 10.4049/jimmunol.179.1.41
Tough, D. F., Sun, S. & Sprent, J. T cell stimulation in vivo by lipopolysaccharide (LPS). J. Exp. Med. 185, 2089–2094 (1997).
doi: 10.1084/jem.185.12.2089
Pudney, J. & Anderson, D. J. Expression of toll-like receptors in genital tract tissues from normal and HIV-infected men. Am. J. Reprod. Immunol. 65, 28–43 (2011).
doi: 10.1111/j.1600-0897.2010.00877.x
Orenstein, J. M. Replication of HIV-1 in vivo and in vitro. Ultrastruct. Pathol. 31, 151–167 (2007).
doi: 10.1080/01913120701344343
Orenstein, J. M., Meltzer, M. S., Phipps, T. & Gendelman, H. E. Cytoplasmic assembly and accumulation of human immunodeficiency virus types 1 and 2 in recombinant human colony-stimulating factor-1-treated human monocytes: an ultrastructural study. J. Virol. 62, 2578–2586 (1988).
pubmed: 3260631
pmcid: 253687
Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).
doi: 10.1016/j.it.2004.09.015
Baxter, A. E. et al. Macrophage infection via selective capture of HIV-1-infected CD4
doi: 10.1016/j.chom.2014.10.010
Calantone, N. et al. Tissue myeloid cells in SIV-infected primates acquire viral DNA through phagocytosis of infected T cells. Immunity 41, 493–502 (2014).
doi: 10.1016/j.immuni.2014.08.014
DiNapoli, S. R. et al. Tissue-resident macrophages can contain replication-competent virus in antiretroviral-naive, SIV-infected Asian macaques. JCI Insight 2, e91214 (2017).
doi: 10.1172/jci.insight.91214
Chomont, N. et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat. Med. 15, 893–900 (2009).
doi: 10.1038/nm.1972
Wiegand, A. et al. Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART. Proc. Natl Acad. Sci. USA 114, E3659–E3668 (2017).
doi: 10.1073/pnas.1617961114
Avalos, C. R. et al. Brain macrophages in simian immunodeficiency virus-infected, antiretroviral-suppressed macaques: a functional latent reservoir. MBio 8, e01186-17 (2017).
doi: 10.1128/mBio.01186-17
Kandathil, A. J. et al. No recovery of replication-competent HIV-1 from human liver macrophages. J. Clin. Invest. 128, 4501–4509 (2018).
doi: 10.1172/JCI121678
Cassetta, L. et al. M1 polarization of human monocyte-derived macrophages restricts pre and postintegration steps of HIV-1 replication. AIDS 27, 1847–1856 (2013).
doi: 10.1097/QAD.0b013e328361d059
Bruner, K. M. et al. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat. Med. 22, 1043–1049 (2016).
doi: 10.1038/nm.4156
Ho, Y. C. et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155, 540–551 (2013).
doi: 10.1016/j.cell.2013.09.020
Real, F., Sennepin, A., Ganor, Y., Schmitt, A. & Bomsel, M. Live imaging of HIV-1 transfer across T cell virological synapse to epithelial cells that promotes stromal macrophage infection. Cell Rep. 23, 1794–1805 (2018).
doi: 10.1016/j.celrep.2018.04.028
Catalfamo, M., Le Saout, C. & Lane, H. C. The role of cytokines in the pathogenesis and treatment of HIV infection. Cytokine Growth Factor Rev. 23, 207–214 (2012).
doi: 10.1016/j.cytogfr.2012.05.007
Clerici, M. & Shearer, G. M. A TH1→TH2 switch is a critical step in the etiology of HIV infection. Immunol. Today 14, 107–111 (1993).
doi: 10.1016/0167-5699(93)90208-3
Houzet, L., Matusali, G. & Dejucq-Rainsford, N. Origins of HIV-infected leukocytes and virions in semen. J. Infect. Dis. 210, S622–S630 (2014).
doi: 10.1093/infdis/jiu328
Galvin, S. R. & Cohen, M. S. The role of sexually transmitted diseases in HIV transmission. Nat. Rev. Microbiol. 2, 33–42 (2004).
doi: 10.1038/nrmicro794
Matusali, G. et al. Detection of simian immunodeficiency virus in semen, urethra, and male reproductive organs during efficient highly active antiretroviral therapy. J. Virol. 89, 5772–5787 (2015).
doi: 10.1128/JVI.03628-14
Dumaurier, M. J., Gratton, S., Wain-Hobson, S. & Cheynier, R. The majority of human immunodeficiency virus type 1 particles present within splenic germinal centres are produced locally. J. Gen. Virol. 86, 3369–3373 (2005).
doi: 10.1099/vir.0.81133-0
Chun, T. W. et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 94, 13193–13197 (1997).
doi: 10.1073/pnas.94.24.13193
Liszewski, M. K., Yu, J. J. & O’Doherty, U. Detecting HIV-1 integration by repetitive-sampling Alu-gag PCR. Methods 47, 254–260 (2009).
doi: 10.1016/j.ymeth.2009.01.002
Folks, T. M., Justement, J., Kinter, A., Dinarello, C. A. & Fauci, A. S. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science 238, 800–802 (1987).
doi: 10.1126/science.3313729
Spina, C. A. et al. An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4
doi: 10.1371/journal.ppat.1003834
Bagasra, O., Wright, S. D., Seshamma, T., Oakes, J. W. & Pomerantz, R. J. CD14 is involved in control of human immunodeficiency virus type 1 expression in latently infected cells by lipopolysaccharide. Proc. Natl Acad. Sci. USA 89, 6285–6289 (1992).
doi: 10.1073/pnas.89.14.6285
Fujihara, M. et al. Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex. Pharmacol. Ther. 100, 171–194 (2003).
doi: 10.1016/j.pharmthera.2003.08.003
Pomerantz, R. J., Feinberg, M. B., Trono, D. & Baltimore, D. Lipopolysaccharide is a potent monocyte/macrophage-specific stimulator of human immunodeficiency virus type 1 expression. J. Exp. Med. 172, 253–261 (1990).
doi: 10.1084/jem.172.1.253
Hirsch, V. M. et al. Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication. J. Virol. 69, 955–967 (1995).
pubmed: 7815563
pmcid: 188664
Salmon, H. et al. Ex vivo imaging of T cells in murine lymph node slices with widefield and confocal microscopes. J. Vis. Exp. 15, e3054 (2011).
Cromey, D. W. Avoiding twisted pixels: ethical guidelines for the appropriate use and manipulation of scientific digital images. Sci. Eng. Ethics 16, 639–667 (2010).
doi: 10.1007/s11948-010-9201-y
Dutertre, C. A. et al. Pivotal role of M-DC8
doi: 10.1182/blood-2012-03-418681
Sennepin, A. et al. NKp44L expression on CD4
doi: 10.1097/QAD.0b013e328361a3fe
Sennepin, A. et al. The human penis is a genuine immunological effector site. Front. Immunol. 8, 1732 (2017).
doi: 10.3389/fimmu.2017.01732