HIV-1 proteins gp120 and tat induce the epithelial–mesenchymal transition in oral and genital mucosal epithelial cells


Autoři: Kathy Lien aff001;  Wasima Mayer aff001;  Rossana Herrera aff001;  Kristina Rosbe aff002;  Sharof M. Tugizov aff001
Působiště autorů: Department of Medicine, University of California–San Francisco, San Francisco, CA, United States of America aff001;  Department of Otolaryngology, University of California–San Francisco, San Francisco, CA, United States of America aff002;  Department of Obstetrics, Gynecology & Reproductive Sciences, University of California–San Francisco, San Francisco, CA, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226343

Souhrn

The oral, cervical, and genital mucosa, covered by stratified squamous epithelia with polarized organization and strong tight and adherens junctions, play a critical role in preventing transmission of viral pathogens, including human immunodeficiency virus (HIV). HIV-1 interaction with mucosal epithelial cells may depolarize epithelia and disrupt their tight and adherens junctions; however, the molecular mechanism of HIV-induced epithelial disruption has not been completely understood. We showed that prolonged interaction of cell-free HIV-1 virions, and viral envelope and transactivator proteins gp120 and tat, respectively, with tonsil, cervical, and foreskin epithelial cells induces an epithelial–mesenchymal transition (EMT). EMT is an epigenetic process leading to the disruption of mucosal epithelia and allowing the paracellular spread of viral and other pathogens. Interaction of cell-free virions and gp120 and tat proteins with epithelial cells substantially reduced E-cadherin expression and activated vimentin and N-cadherin expression, which are well-known mesenchymal markers. HIV gp120- and tat-induced EMT was mediated by SMAD2 phosphorylation and activation of transcription factors Slug, Snail, Twist1 and ZEB1. Activation of TGF-β and MAPK signaling by gp120, tat, and cell-free HIV virions revealed the critical roles of these signaling pathways in EMT induction. gp120- and tat-induced EMT cells were highly migratory via collagen-coated membranes, which is one of the main features of mesenchymal cells. Inhibitors of TGF-β1 and MAPK signaling reduced HIV-induced EMT, suggesting that inactivation of these signaling pathways may restore the normal barrier function of mucosal epithelia.

Klíčová slova:

Epithelial cells – HIV-1 – Keratinocytes – MAPK signaling cascades – TGF-beta signaling cascade – Tonsils – Vimentin


Zdroje

1. Schluter H, Wepf R, Moll I, Franke WW. Sealing the live part of the skin: the integrated meshwork of desmosomes, tight junctions and curvilinear ridge structures in the cells of the uppermost granular layer of the human epidermis. Eur J Cell Biol. 2004;83(11–12):655–65. doi: 10.1078/0171-9335-00434 15679110.

2. Langbein L, Pape UF, Grund C, Kuhn C, Praetzel S, Moll I, et al. Tight junction-related structures in the absence of a lumen: occludin, claudins and tight junction plaque proteins in densely packed cell formations of stratified epithelia and squamous cell carcinomas. Eur J Cell Biol. 2003;82(8):385–400. doi: 10.1078/0171-9335-00330 14533737.

3. Langbein L, Grund C, Kuhn C, Praetzel S, Kartenbeck J, Brandner JM, et al. Tight junctions and compositionally related junctional structures in mammalian stratified epithelia and cell cultures derived therefrom. Eur J Cell Biol. 2002;81(8):419–35. doi: 10.1078/0171-9335-00270 12234014.

4. Brandner JM, Kief S, Grund C, Rendl M, Houdek P, Kuhn C, et al. Organization and formation of the tight junction system in human epidermis and cultured keratinocytes. Eur J Cell Biol. 2002;81(5):253–63. doi: 10.1078/0171-9335-00244 12067061.

5. Takano K, Kojima T, Go M, Murata M, Ichimiya S, Himi T, et al. HLA-DR- and CD11c-positive dendritic cells penetrate beyond well-developed epithelial tight junctions in human nasal mucosa of allergic rhinitis. J Histochem Cytochem. 2005;53(5):611–9. doi: 10.1369/jhc.4A6539.2005 15872054.

6. Blaskewicz CD, Pudney J, Anderson DJ. Structure and function of intercellular junctions in human cervical and vaginal mucosal epithelia. Biology of reproduction. 2011;85(1):97–104. Epub 2011/04/08. doi: 10.1095/biolreprod.110.090423 21471299; PubMed Central PMCID: PMC3123383.

7. Tugizov SM, Herrera R, Chin-Hong P, Veluppillai P, Greenspan D, Michael Berry J, et al. HIV-associated disruption of mucosal epithelium facilitates paracellular penetration by human papillomavirus. Virology. 2013;446(1–2):378–88. Epub 2013/10/01. doi: 10.1016/j.virol.2013.08.018 24074602.

8. Tugizov SM, Herrera R, Veluppillai P, Greenspan D, Soros V, Greene WC, et al. HIV is inactivated after transepithelial migration via adult oral epithelial cells but not fetal epithelial cells. Virology. 2011;409(2):211–22. Epub 2010/11/09. doi: 10.1016/j.virol.2010.10.004 21056450; PubMed Central PMCID: PMC3034249.

9. Tugizov SM, Herrera R, Veluppillai P, Greenspan D, Soros V, Greene WC, et al. Differential transmission of HIV traversing fetal oral/intestinal epithelia and adult oral epithelia. Journal of Virology. 2012;86(5):2556–70. Epub 2011/12/30. doi: 10.1128/JVI.06578-11 22205732; PubMed Central PMCID: PMC3302289.

10. Go M, Kojima T, Takano K, Murata M, Ichimiya S, Tsubota H, et al. Expression and function of tight junctions in the crypt epithelium of human palatine tonsils. J Histochem Cytochem. 2004;52(12):1627–38. doi: 10.1369/jhc.4A6339.2004 15557217.

11. Sawada N, Murata M, Kikuchi K, Osanai M, Tobioka H, Kojima T, et al. Tight junctions and human diseases. Med Electron Microsc. 2003;36(3):147–56. Epub 2003/09/25. doi: 10.1007/s00795-003-0219-y 14505058.

12. Epple HJ, Allers K, Troger H, Kuhl A, Erben U, Fromm M, et al. Acute HIV infection induces mucosal infiltration with CD4+ and CD8+ T cells, epithelial apoptosis, and a mucosal barrier defect. Gastroenterology. 2010;139(4):1289–300. Epub 2010/07/06. doi: 10.1053/j.gastro.2010.06.065 20600014.

13. Epple HJ, Schneider T, Troeger H, Kunkel D, Allers K, Moos V, et al. Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients. Gut. 2009;58(2):220–7. Epub 2008/10/22. doi: 10.1136/gut.2008.150425 18936106.

14. Assimakopoulos SF, Dimitropoulou D, Marangos M, Gogos CA. Intestinal barrier dysfunction in HIV infection: pathophysiology, clinical implications and potential therapies. Infection. 2014;42(6):951–9. Epub 2014/07/30. doi: 10.1007/s15010-014-0666-5 25070877.

15. Kapembwa MS, Fleming SC, Orr M, Wells C, Bland M, Back D, et al. Impaired absorption of zidovudine in patients with AIDS-related small intestinal disease. Aids. 1996;10(13):1509–14. doi: 10.1097/00002030-199611000-00008 8931785.

16. Obinna FC, Cook G, Beale T, Dave S, Cunningham D, Fleming SC, et al. Comparative assessment of small intestinal and colonic permeability in HIV-infected homosexual men. Aids. 1995;9(9):1009–16. doi: 10.1097/00002030-199509000-00005 8527072.

17. Kapembwa MS, Fleming SC, Sewankambo N, Serwadda D, Lucas S, Moody A, et al. Altered small-intestinal permeability associated with diarrhoea in human-immunodeficiency-virus-infected Caucasian and African subjects. Clin Sci (Lond). 1991;81(3):327–34. doi: 10.1042/cs0810327 1655333.

18. Stockmann M, Fromm M, Schmitz H, Schmidt W, Riecken EO, Schulzke JD. Duodenal biopsies of HIV-infected patients with diarrhoea exhibit epithelial barrier defects but no active secretion. Aids. 1998;12(1):43–51. doi: 10.1097/00002030-199801000-00006 9456254.

19. Tugizov S. Human immunodeficiency virus-associated disruption of mucosal barriers and its role in HIV transmission and pathogenesis of HIV/AIDS disease. Tissue Barriers. 2016;4(3):e1159276. doi: 10.1080/21688370.2016.1159276 27583187; PubMed Central PMCID: PMC4993574.

20. Nazli A, Chan O, Dobson-Belaire WN, Ouellet M, Tremblay MJ, Gray-Owen SD, et al. Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS pathogens. 2010;6(4):e1000852. Epub 2010/04/14. doi: 10.1371/journal.ppat.1000852 20386714; PubMed Central PMCID: PMC2851733.

21. Sufiawati I, Tugizov SM. HIV-Associated Disruption of Tight and Adherens Junctions of Oral Epithelial Cells Facilitates HSV-1 Infection and Spread. PloS one. 2014;9(2):e88803. Epub 2014/03/04. doi: 10.1371/journal.pone.0088803 24586397; PubMed Central PMCID: PMC3931628.

22. Sufiawati I, Tugizov SM. HIV-induced matrix metalloproteinase-9 activation through mitogen-activated protein kinase signalling promotes HSV-1 cell-to-cell spread in oral epithelial cells. Journal of General Virology. 2018;In press.

23. Pope M, Haase AT. Transmission, acute HIV-1 infection and the quest for strategies to prevent infection. Nat Med. 2003;9(7):847–52. Epub 2003/07/02. doi: 10.1038/nm0703-847 [pii]. 12835704.

24. Dayanithi G, Yahi N, Baghdiguian S, Fantini J. Intracellular calcium release induced by human immunodeficiency virus type 1 (HIV-1) surface envelope glycoprotein in human intestinal epithelial cells: a putative mechanism for HIV-1 enteropathy. Cell Calcium. 1995;18(1):9–18. Epub 1995/07/01. doi: 10.1016/0143-4160(95)90041-1 7585886.

25. Pu H, Tian J, Andras IE, Hayashi K, Flora G, Hennig B, et al. HIV-1 Tat protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK 1/2 activation. J Cereb Blood Flow Metab. 2005;25(10):1325–35. doi: 10.1038/sj.jcbfm.9600125 15829913.

26. Pu H, Tian J, Flora G, Lee YW, Nath A, Hennig B, et al. HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain. Mol Cell Neurosci. 2003;24(1):224–37. doi: 10.1016/s1044-7431(03)00171-4 14550782.

27. Ikenouchi J, Matsuda M, Furuse M, Tsukita S. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci. 2003;116(Pt 10):1959–67. Epub 2003/04/02. doi: 10.1242/jcs.00389 12668723.

28. Antony J, Thiery JP, Huang RY. Epithelial-to-mesenchymal transition: lessons from development, insights into cancer and the potential of EMT-subtype based therapeutic intervention. Phys Biol. 2019;16(4):041004. doi: 10.1088/1478-3975/ab157a 30939460.

29. Lim J, Thiery JP. Epithelial-mesenchymal transitions: insights from development. Development. 2012;139(19):3471–86. doi: 10.1242/dev.071209 22949611.

30. Moustakas A, Heldin CH. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007;98(10):1512–20. Epub 2007/07/25. doi: 10.1111/j.1349-7006.2007.00550.x 17645776.

31. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90. doi: 10.1016/j.cell.2009.11.007 19945376.

32. Ocana OH, Nieto MA. Epithelial plasticity, stemness and pluripotency. Cell Res. 2010;20(10):1086–8. Epub 2010/09/08. doi: 10.1038/cr.2010.127 20820188.

33. Nieto MA, Cano A. The epithelial-mesenchymal transition under control: global programs to regulate epithelial plasticity. Semin Cancer Biol. 2012;22(5–6):361–8. Epub 2012/05/23. doi: 10.1016/j.semcancer.2012.05.003 22613485.

34. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. The Journal of clinical investigation. 2009;119(6):1420–8. Epub 2009/06/03. doi: 10.1172/JCI39104 19487818; PubMed Central PMCID: PMC2689101.

35. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nature reviews Molecular cell biology. 2014;15(3):178–96. Epub 2014/02/22. doi: 10.1038/nrm3758 24556840; PubMed Central PMCID: PMC4240281.

36. Moustakas A, Heldin CH. Mechanisms of TGFbeta-Induced Epithelial-Mesenchymal Transition. J Clin Med. 2016;5(7). Epub 2016/07/02. doi: 10.3390/jcm5070063 27367735; PubMed Central PMCID: PMC4961994.

37. Wang H, Zhang G, Zhang H, Zhang F, Zhou B, Ning F, et al. Acquisition of epithelial-mesenchymal transition phenotype and cancer stem cell-like properties in cisplatin-resistant lung cancer cells through AKT/beta-catenin/Snail signaling pathway. Eur J Pharmacol. 2014;723:156–66. Epub 2013/12/18. doi: 10.1016/j.ejphar.2013.12.004 24333218.

38. Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014;7(344):re8. Epub 2014/09/25. doi: 10.1126/scisignal.2005189 25249658; PubMed Central PMCID: PMC4372086.

39. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20(2):69–84. Epub 2018/11/22. doi: 10.1038/s41580-018-0080-4 30459476.

40. Talbot LJ, Bhattacharya SD, Kuo PC. Epithelial-mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies. Int J Biochem Mol Biol. 2012;3(2):117–36. Epub 2012/07/10. 22773954; PubMed Central PMCID: PMC3388731.

41. Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. The New England journal of medicine. 2000;342(18):1350–8. Epub 2000/05/04. doi: 10.1056/NEJM200005043421807 10793168.

42. Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochimica et Biophysica Acta. 2008;1782(4):197–228. Epub 2008/03/04. doi: 10.1016/j.bbadis.2008.01.006 18313409.

43. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96. Epub 2014/02/22. doi: 10.1038/nrm3758 24556840; PubMed Central PMCID: PMC4240281.

44. Dave N, Guaita-Esteruelas S, Gutarra S, Frias A, Beltran M, Peiro S, et al. Functional cooperation between Snail1 and twist in the regulation of ZEB1 expression during epithelial to mesenchymal transition. J Biol Chem. 2011;286(14):12024–32. Epub 2011/02/15. doi: 10.1074/jbc.M110.168625 21317430; PubMed Central PMCID: PMC3069405.

45. Meulmeester E, Ten Dijke P. The dynamic roles of TGF-beta in cancer. The Journal of pathology. 2011;223(2):205–18. Epub 2010/10/20. doi: 10.1002/path.2785 20957627.

46. Wendt MK, Tian M, Schiemann WP. Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression. Cell and tissue research. 2012;347(1):85–101. Epub 2011/06/22. doi: 10.1007/s00441-011-1199-1 21691718.

47. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005;132(14):3151–61. Epub 2005/06/29. doi: 10.1242/dev.01907 15983400.

48. Peinado H, Marin F, Cubillo E, Stark HJ, Fusenig N, Nieto MA, et al. Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J Cell Sci. 2004;117(Pt 13):2827–39. Epub 2004/06/01. doi: 10.1242/jcs.01145 15169839.

49. Hennig G, Behrens J, Truss M, Frisch S, Reichmann E, Birchmeier W. Progression of carcinoma cells is associated with alterations in chromatin structure and factor binding at the E-cadherin promoter in vivo. Oncogene. 1995;11(3):475–84. Epub 1995/08/03. 7630631.

50. Stivarou T, Patsavoudi E. Extracellular molecules involved in cancer cell invasion. Cancers (Basel). 2015;7(1):238–65. doi: 10.3390/cancers7010238 25629807; PubMed Central PMCID: PMC4381257.

51. Xia S, Wang C, Postma EL, Yang Y, Ni X, Zhan W. Fibronectin 1 promotes migration and invasion of papillary thyroid cancer and predicts papillary thyroid cancer lymph node metastasis. Onco Targets Ther. 2017;10:1743–55. doi: 10.2147/OTT.S122009 28367057; PubMed Central PMCID: PMC5370387.

52. Ohnishi T, Hiraga S, Izumoto S, Matsumura H, Kanemura Y, Arita N, et al. Role of fibronectin-stimulated tumor cell migration in glioma invasion in vivo: clinical significance of fibronectin and fibronectin receptor expressed in human glioma tissues. Clin Exp Metastasis. 1998;16(8):729–41. doi: 10.1023/a:1006532812408 10211986.

53. van Zijl F, Krupitza G, Mikulits W. Initial steps of metastasis: cell invasion and endothelial transmigration. Mutat Res. 2011;728(1–2):23–34. doi: 10.1016/j.mrrev.2011.05.002 21605699; PubMed Central PMCID: PMC4028085.

54. Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol. 2000;148(4):779–90. doi: 10.1083/jcb.148.4.779 10684258; PubMed Central PMCID: PMC2169367.

55. Sandig M, Voura EB, Kalnins VI, Siu CH. Role of cadherins in the transendothelial migration of melanoma cells in culture. Cell Motil Cytoskeleton. 1997;38(4):351–64. doi: 10.1002/(SICI)1097-0169(1997)38:4<351::AID-CM5>3.0.CO;2-6 9415377.

56. Moustakas A, Heldin CH. Non-Smad TGF-beta signals. J Cell Sci. 2005;118(Pt 16):3573–84. Epub 2005/08/18. doi: 10.1242/jcs.02554 16105881.

57. Mu Y, Gudey SK, Landstrom M. Non-Smad signaling pathways. Cell Tissue Res. 2012;347(1):11–20. Epub 2011/06/28. doi: 10.1007/s00441-011-1201-y 21701805.

58. Lee MK, Pardoux C, Hall MC, Lee PS, Warburton D, Qing J, et al. TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J. 2007;26(17):3957–67. Epub 2007/08/04. doi: 10.1038/sj.emboj.7601818 17673906; PubMed Central PMCID: PMC1994119.

59. Cordenonsi M, Montagner M, Adorno M, Zacchigna L, Martello G, Mamidi A, et al. Integration of TGF-beta and Ras/MAPK signaling through p53 phosphorylation. Science. 2007;315(5813):840–3. Epub 2007/01/20. doi: 10.1126/science.1135961 17234915.

60. Matsuura I, Wang G, He D, Liu F. Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3. Biochemistry. 2005;44(37):12546–53. Epub 2005/09/15. doi: 10.1021/bi050560g 16156666.

61. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol. 2002;156(2):299–313. Epub 2002/01/16. doi: 10.1083/jcb.200109037 11790801; PubMed Central PMCID: PMC2199233.

62. Mulder KM. Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev. 2000;11(1–2):23–35. Epub 2000/03/10. doi: 10.1016/s1359-6101(99)00026-x 10708950.

63. Hong J, Zhou J, Fu J, He T, Qin J, Wang L, et al. Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res. 2011;71(11):3980–90. Epub 2011/04/20. doi: 10.1158/0008-5472.CAN-10-2914 21502402; PubMed Central PMCID: PMC3107354.

64. Chapnick DA, Warner L, Bernet J, Rao T, Liu X. Partners in crime: the TGFbeta and MAPK pathways in cancer progression. Cell Biosci. 2011;1:42. Epub 2011/12/30. doi: 10.1186/2045-3701-1-42 22204556; PubMed Central PMCID: PMC3275500.

65. Beachler DC, Weber KM, Margolick JB, Strickler HD, Cranston RD, Burk RD, et al. Risk Factors for Oral HPV Infection among a High Prevalence Population of HIV-Positive and At-Risk HIV-Negative Adults. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2011. Epub 2011/11/03. doi: 10.1158/1055-9965.EPI-11-0734 22045700.

66. Agrawal Y, Koch WM, Xiao W, Westra WH, Trivett AL, Symer DE, et al. Oral human papillomavirus infection before and after treatment for human papillomavirus 16-positive and human papillomavirus 16-negative head and neck squamous cell carcinoma. Clin Cancer Res. 2008;14(21):7143–50. Epub 2008/11/05. doi: 10.1158/1078-0432.CCR-08-0498 18981014; PubMed Central PMCID: PMC2598779.

67. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612–9. Epub 2008/02/01. doi: 10.1200/JCO.2007.14.1713 18235120.

68. D'Souza G, Agrawal Y, Halpern J, Bodison S, Gillison ML. Oral sexual behaviors associated with prevalent oral human papillomavirus infection. The Journal of infectious diseases. 2009;199(9):1263–9. Epub 2009/03/27. doi: 10.1086/597755 19320589.

69. D'Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Case-control study of human papillomavirus and oropharyngeal cancer. The New England journal of medicine. 2007;356(19):1944–56. Epub 2007/05/15. doi: 10.1056/NEJMoa065497 17494927.

70. Gillison ML. Human papillomavirus-related diseases: oropharynx cancers and potential implications for adolescent HPV vaccination. J Adolesc Health. 2008;43(4 Suppl):S52–60. Epub 2008/10/01. doi: 10.1016/j.jadohealth.2008.07.002 18809146; PubMed Central PMCID: PMC3037092.

71. Kreimer AR, Alberg AJ, Daniel R, Gravitt PE, Viscidi R, Garrett ES, et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. The Journal of infectious diseases. 2004;189(4):686–98. Epub 2004/02/10. doi: 10.1086/381504 14767823.

72. Gillison ML. Oropharyngeal cancer: a potential consequence of concomitant HPV and HIV infection. Current opinion in oncology. 2009;21(5):439–44. Epub 2009/07/10. doi: 10.1097/CCO.0b013e32832f3e1b 19587593.

73. Beachler DC, D'Souza G. Oral human papillomavirus infection and head and neck cancers in HIV-infected individuals. Current opinion in oncology. 2013;25(5):503–10. Epub 2013/07/16. doi: 10.1097/CCO.0b013e32836242b4 23852381; PubMed Central PMCID: PMC3896303.

74. Beachler DC, D'Souza G, Sugar EA, Xiao W, Gillison ML. Natural history of anal vs oral HPV infection in HIV-infected men and women. The Journal of infectious diseases. 2013;208(2):330–9. Epub 2013/04/19. doi: 10.1093/infdis/jit170 23596319; PubMed Central PMCID: PMC3685232.

75. Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. Journal of the National Cancer Institute. 2000;92(18):1500–10. Epub 2000/09/21. doi: 10.1093/jnci/92.18.1500 10995805.

76. Clifford GM, Polesel J, Rickenbach M, Dal Maso L, Keiser O, Kofler A, et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. Journal of the National Cancer Institute. 2005;97(6):425–32. Epub 2005/03/17. doi: 10.1093/jnci/dji072 15770006.

77. Engels EA, Biggar RJ, Hall HI, Cross H, Crutchfield A, Finch JL, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. International journal of cancer Journal international du cancer. 2008;123(1):187–94. Epub 2008/04/26. doi: 10.1002/ijc.23487 18435450.

78. Powles T, Robinson D, Stebbing J, Shamash J, Nelson M, Gazzard B, et al. Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection. J Clin Oncol. 2009;27(6):884–90. Epub 2008/12/31. doi: 10.1200/JCO.2008.19.6626 19114688.

79. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59–67. Epub 2007/07/10. doi: 10.1016/S0140-6736(07)61050-2 17617273.

80. Machalek DA, Poynten M, Jin F, Fairley CK, Farnsworth A, Garland SM, et al. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. The lancet oncology. 2012;13(5):487–500. Epub 2012/03/27. doi: 10.1016/S1470-2045(12)70080-3 22445259.

81. Palefsky JM. Anal cancer prevention in HIV-positive men and women. Current opinion in oncology. 2009;21(5):433–8. Epub 2009/07/10. doi: 10.1097/CCO.0b013e32832f511a 19587592.

82. Palefsky JM. Antiretroviral therapy and anal cancer: the good, the bad, and the unknown. Sexually transmitted diseases. 2012;39(7):501–3. Epub 2012/06/15. doi: 10.1097/OLQ.0b013e31825f7921 22695317.

83. Mallari AO, Schwartz TM, Luque AE, Polashenski PS, Rauh SM, Corales RB. Anal cancer screening in HIV-infected patients: is it time to screen them all? Dis Colon Rectum. 2012;55(12):1244–50. Epub 2012/11/09. doi: 10.1097/DCR.0b013e31826ab4fb 23135582.

84. Denny LA, Franceschi S, de Sanjose S, Heard I, Moscicki AB, Palefsky J. Human papillomavirus, human immunodeficiency virus and immunosuppression. Vaccine. 2012;30 Suppl 5:F168–74. Epub 2012/12/05. doi: 10.1016/j.vaccine.2012.06.045 23199960.

85. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7(2):131–42. doi: 10.1038/nrm1835 16493418.

86. Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, et al. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature. 1995;375(6531):497–500. doi: 10.1038/375497a0 7539892.

87. Xiao H, Neuveut C, Tiffany HL, Benkirane M, Rich EA, Murphy PM, et al. Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1. Proc Natl Acad Sci U S A. 2000;97(21):11466–71. doi: 10.1073/pnas.97.21.11466 11027346.

88. Rychert J, Strick D, Bazner S, Robinson J, Rosenberg E. Detection of HIV gp120 in plasma during early HIV infection is associated with increased proinflammatory and immunoregulatory cytokines. AIDS research and human retroviruses. 2010;26(10):1139–45. Epub 2010/08/21. doi: 10.1089/aid.2009.0290 20722464; PubMed Central PMCID: PMC2982714.

89. Poggi A, Zocchi MR. HIV-1 Tat triggers TGF-beta production and NK cell apoptosis that is prevented by pertussis toxin B. Clin Dev Immunol. 2006;13(2–4):369–72. Epub 2006/12/13. doi: 10.1080/17402520600645712 17162379; PubMed Central PMCID: PMC2270756.

90. Ulich C, Dunne A, Parry E, Hooker CW, Gaynor RB, Harrich D. Functional domains of Tat required for efficient human immunodeficiency virus type 1 reverse transcription. Journal of Virology. 1999;73(3):2499–508. Epub 1999/02/11. 9971835; PubMed Central PMCID: PMC104497.

91. Toschi E, Bacigalupo I, Strippoli R, Chiozzini C, Cereseto A, Falchi M, et al. HIV-1 Tat regulates endothelial cell cycle progression via activation of the Ras/ERK MAPK signaling pathway. Mol Biol Cell. 2006;17(4):1985–94. doi: 10.1091/mbc.E05-08-0717 16436505.

92. Modesti N, Garcia J, Debouck C, Peterlin M, Gaynor R. Trans-dominant Tat mutants with alterations in the basic domain inhibit HIV-1 gene expression. The New biologist. 1991;3(8):759–68. Epub 1991/08/01. 1931822.

93. Fletcher CV, Staskus K, Wietgrefe SW, Rothenberger M, Reilly C, Chipman JG, et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci U S A. 2014;111(6):2307–12. doi: 10.1073/pnas.1318249111 24469825; PubMed Central PMCID: PMC3926074.

94. Huang Y, Hoque MT, Jenabian MA, Vyboh K, Whyte SK, Sheehan NL, et al. Antiretroviral drug transporters and metabolic enzymes in human testicular tissue: potential contribution to HIV-1 sanctuary site. J Antimicrob Chemother. 2016;71(7):1954–65. doi: 10.1093/jac/dkw046 27076103; PubMed Central PMCID: PMC4896405.

95. Lorenzo-Redondo R, Fryer HR, Bedford T, Kim EY, Archer J, Kosakovsky Pond SL, et al. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature. 2016;530(7588):51–6. doi: 10.1038/nature16933 26814962; PubMed Central PMCID: PMC4865637.

96. Di Mascio M, Srinivasula S, Bhattacharjee A, Cheng L, Martiniova L, Herscovitch P, et al. Antiretroviral tissue kinetics: in vivo imaging using positron emission tomography. Antimicrob Agents Chemother. 2009;53(10):4086–95. doi: 10.1128/AAC.00419-09 19667288; PubMed Central PMCID: PMC2764156.

97. Bates RC, Mercurio AM. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell. 2003;14(5):1790–800. Epub 2003/06/13. doi: 10.1091/mbc.E02-09-0583 12802055; PubMed Central PMCID: PMC165077.

98. Wang H, Wang HS, Zhou BH, Li CL, Zhang F, Wang XF, et al. Epithelial-mesenchymal transition (EMT) induced by TNF-alpha requires AKT/GSK-3beta-mediated stabilization of snail in colorectal cancer. PLoS One. 2013;8(2):e56664. Epub 2013/02/23. doi: 10.1371/journal.pone.0056664 23431386; PubMed Central PMCID: PMC3576347.

99. Ho MY, Tang SJ, Chuang MJ, Cha TL, Li JY, Sun GH, et al. TNF-alpha induces epithelial-mesenchymal transition of renal cell carcinoma cells via a GSK3beta-dependent mechanism. Mol Cancer Res. 2012;10(8):1109–19. Epub 2012/06/19. doi: 10.1158/1541-7786.MCR-12-0160 22707636.

100. Lv N, Gao Y, Guan H, Wu D, Ding S, Teng W, et al. Inflammatory mediators, tumor necrosis factor-alpha and interferon-gamma, induce EMT in human PTC cell lines. Oncol Lett. 2015;10(4):2591–7. Epub 2015/12/02. doi: 10.3892/ol.2015.3518 26622895; PubMed Central PMCID: PMC4580000.

101. Rodriguez-Inigo E, Jimenez E, Bartolome J, Ortiz-Movilla N, Bartolome Villar B, Jose Arrieta J, et al. Detection of human immunodeficiency virus type 1 RNA by in situ hybridization in oral mucosa epithelial cells from anti-HIV-1 positive patients. J Med Virol. 2005;77(1):17–22. doi: 10.1002/jmv.20409 16032727.

102. Chou LL, Epstein J, Cassol SA, West DM, He W, Firth JD. Oral mucosal Langerhans' cells as target, effector and vector in HIV infection. J Oral Pathol Med. 2000;29(8):394–402. doi: 10.1034/j.1600-0714.2000.290805.x 10972348

103. Goto Y, Yeh CK, Notkins AL, Prabhakar BS. Detection of proviral sequences in saliva of patients infected with human immunodeficiency virus type 1. AIDS Res Hum Retroviruses. 1991;7(3):343–7. doi: 10.1089/aid.1991.7.343 2064831

104. Kakizawa J, Ushijima H, Oka S, Ikeda Y, Schroder HC, Muller WE. Detection of human immunodeficiency virus-1 DNA, RNA and antibody, and occult blood in inactivated saliva: availability of the filter paper disk method. Acta Paediatr Jpn. 1996;38(3):218–23. doi: 10.1111/j.1442-200x.1996.tb03473.x 8741309

105. Liuzzi G, Chirianni A, Clementi M, Bagnarelli P, Valenza A, Cataldo PT, et al. Analysis of HIV-1 load in blood, semen and saliva: evidence for different viral compartments in a cross-sectional and longitudinal study. Aids. 1996;10(14):F51–6. doi: 10.1097/00002030-199612000-00001 8970677

106. Maticic M, Poljak M, Kramar B, Tomazic J, Vidmar L, Zakotnik B, et al. Proviral HIV-1 DNA in gingival crevicular fluid of HIV-1-infected patients in various stages of HIV disease. J Dent Res. 2000;79(7):1496–501. doi: 10.1177/00220345000790071101 11005734

107. Qureshi MN, Barr CE, Hewlitt I, Boorstein R, Kong F, Bagasra O, et al. Detection of HIV in oral mucosal cells. Oral Dis. 1997;3 Suppl 1:S73-8.

108. Qureshi MN, Barr CE, Seshamma T, Reidy J, Pomerantz RJ, Bagasra O. Infection of oral mucosal cells by human immunodeficiency virus type 1 in seropositive persons. J Infect Dis. 1995;171(1):190–3. doi: 10.1093/infdis/171.1.190 7798662

109. Zuckerman RA, Whittington WL, Celum CL, Collis T, Lucchetti A, Sanchez JL, et al. Factors associated with oropharyngeal human immunodeficiency virus shedding. J Infect Dis. 2003;188(1):142–5. doi: 10.1086/375741 12825183

110. Nuovo GJ, Forde A, MacConnell P, Fahrenwald R. In situ detection of PCR-amplified HIV-1 nucleic acids and tumor necrosis factor cDNA in cervical tissues. Am J Pathol. 1993;143(1):40–8. 8317555

111. Clemetson DB, Moss GB, Willerford DM, Hensel M, Emonyi W, Holmes KK, et al. Detection of HIV DNA in cervical and vaginal secretions. Prevalence and correlates among women in Nairobi, Kenya. JAMA: the journal of the American Medical Association. 1993;269(22):2860–4. Epub 1993/06/09. 8497089.

112. Sonza S, Mutimer HP, Oelrichs R, Jardine D, Harvey K, Dunne A, et al. Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. Aids. 2001;15(1):17–22. doi: 10.1097/00002030-200101050-00005 11192864.

113. Henning TR, Kissinger P, Lacour N, Meyaski-Schluter M, Clark R, Amedee AM. Elevated cervical white blood cell infiltrate is associated with genital HIV detection in a longitudinal cohort of antiretroviral therapy-adherent women. The Journal of infectious diseases. 2010;202(10):1543–52. Epub 2010/10/12. doi: 10.1086/656720 20925530.

114. Crowe SM, Sonza S. HIV-1 can be recovered from a variety of cells including peripheral blood monocytes of patients receiving highly active antiretroviral therapy: a further obstacle to eradication. Journal of leukocyte biology. 2000;68(3):345–50. Epub 2000/09/14. 10985250.

115. Jayakumar P, Berger I, Autschbach F, Weinstein M, Funke B, Verdin E, et al. Tissue-resident macrophages are productively infected ex vivo by primary X4 isolates of human immunodeficiency virus type 1. J Virol. 2005;79(8):5220–6. doi: 10.1128/JVI.79.8.5220-5226.2005 15795306.

116. Santosuosso M, Righi E, Lindstrom V, Leblanc PR, Poznansky MC. HIV-1 envelope protein gp120 is present at high concentrations in secondary lymphoid organs of individuals with chronic HIV-1 infection. The Journal of infectious diseases. 2009;200(7):1050–3. Epub 2009/08/25. doi: 10.1086/605695 19698075.

117. Oh SK, Cruikshank WW, Raina J, Blanchard GC, Adler WH, Walker J, et al. Identification of HIV-1 envelope glycoprotein in the serum of AIDS and ARC patients. Journal of acquired immune deficiency syndromes. 1992;5(3):251–6. Epub 1992/01/01. 1740750.

118. Montagnier L, Clavel F, Krust B, Chamaret S, Rey F, Barre-Sinoussi F, et al. Identification and antigenicity of the major envelope glycoprotein of lymphadenopathy-associated virus. Virology. 1985;144(1):283–9. Epub 1985/07/15. doi: 10.1016/0042-6822(85)90326-5 2414918.

119. Fujii Y, Otake K, Tashiro M, Adachi A. Soluble Nef antigen of HIV-1 is cytotoxic for human CD4+ T cells. FEBS letters. 1996;393(1):93–6. Epub 1996/09/09. doi: 10.1016/0014-5793(96)00859-9 8804432.

120. Ali SA, Huang MB, Campbell PE, Roth WW, Campbell T, Khan M, et al. Genetic characterization of HIV type 1 Nef-induced vesicle secretion. AIDS research and human retroviruses. 2010;26(2):173–92. Epub 2010/02/17. doi: 10.1089/aid.2009.0068 20156100; PubMed Central PMCID: PMC2835390.

121. Elrefaei M, Burke CM, Baker CA, Jones NG, Bousheri S, Bangsberg DR, et al. HIV-specific TGF-beta-positive CD4+ T cells do not express regulatory surface markers and are regulated by CTLA-4. AIDS research and human retroviruses. 2010;26(3):329–37. Epub 2010/05/04. doi: 10.1089/aid.2009.0149 20433405; PubMed Central PMCID: PMC2933167.

122. Elrefaei M, Burke CM, Baker CA, Jones NG, Bousheri S, Bangsberg DR, et al. TGF-beta and IL-10 production by HIV-specific CD8+ T cells is regulated by CTLA-4 signaling on CD4+ T cells. PloS one. 2009;4(12):e8194. Epub 2009/12/18. doi: 10.1371/journal.pone.0008194 20016783; PubMed Central PMCID: PMC2791208.

123. Kekow J, Wachsman W, McCutchan JA, Cronin M, Carson DA, Lotz M. Transforming growth factor beta and noncytopathic mechanisms of immunodeficiency in human immunodeficiency virus infection. Proceedings of the National Academy of Sciences of the United States of America. 1990;87(21):8321–5. Epub 1990/11/01. doi: 10.1073/pnas.87.21.8321 1700428; PubMed Central PMCID: PMC54947.

124. Amarnath S, Dong L, Li J, Wu Y, Chen W. Endogenous TGF-beta activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-1-infected human CD4+CD25- T cells. Retrovirology. 2007;4:57. Epub 2007/08/11. doi: 10.1186/1742-4690-4-57 17688698; PubMed Central PMCID: PMC2096626.

125. Garba ML, Pilcher CD, Bingham AL, Eron J, Frelinger JA. HIV antigens can induce TGF-beta(1)-producing immunoregulatory CD8+ T cells. Journal of Immunology. 2002;168(5):2247–54. Epub 2002/02/23. doi: 10.4049/jimmunol.168.5.2247 11859112.

126. Zocchi MR, Contini P, Alfano M, Poggi A. Pertussis toxin (PTX) B subunit and the nontoxic PTX mutant PT9K/129G inhibit Tat-induced TGF-beta production by NK cells and TGF-beta-mediated NK cell apoptosis. Journal of Immunology. 2005;174(10):6054–61. Epub 2005/05/10. doi: 10.4049/jimmunol.174.10.6054 15879099.

127. Hu R, Oyaizu N, Than S, Kalyanaraman VS, Wang XP, Pahwa S. HIV-1 gp160 induces transforming growth factor-beta production in human PBMC. Clin Immunol Immunopathol. 1996;80(3 Pt 1):283–9. Epub 1996/09/01. doi: 10.1006/clin.1996.0125 8811049.

128. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14(2):163–76. Epub 2000/02/01. 10652271; PubMed Central PMCID: PMC316345.

129. Kobayashi T, Kim H, Liu X, Sugiura H, Kohyama T, Fang Q, et al. Matrix metalloproteinase-9 activates TGF-beta and stimulates fibroblast contraction of collagen gels. Am J Physiol Lung Cell Mol Physiol. 2014;306(11):L1006–15. Epub 2014/04/08. doi: 10.1152/ajplung.00015.2014 24705725; PubMed Central PMCID: PMC4042193.

130. Birchenall-Roberts MC, Ruscetti FW, Kasper J, Lee HD, Friedman R, Geiser A, et al. Transcriptional regulation of the transforming growth factor beta 1 promoter by v-src gene products is mediated through the AP-1 complex. Molecular and Cellular Biology. 1990;10(9):4978–83. Epub 1990/09/01. doi: 10.1128/mcb.10.9.4978 2117705; PubMed Central PMCID: PMC361127.

131. Glauser DA, Schlegel W. Sequential actions of ERK1/2 on the AP-1 transcription factor allow temporal integration of metabolic signals in pancreatic beta cells. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2007;21(12):3240–9. Epub 2007/05/17. doi: 10.1096/fj.06-7798com 17504975.

132. Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. The Journal of biological chemistry. 1995;270(28):16483–6. Epub 1995/07/14. doi: 10.1074/jbc.270.28.16483 7622446.

133. Lee C, Liu QH, Tomkowicz B, Yi Y, Freedman BD, Collman RG. Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways. Journal of leukocyte biology. 2003;74(5):676–82. Epub 2003/09/10. doi: 10.1189/jlb.0503206 12960231.

134. Del Corno M, Liu QH, Schols D, de Clercq E, Gessani S, Freedman BD, et al. HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling. Blood. 2001;98(10):2909–16. Epub 2001/11/08. doi: 10.1182/blood.v98.10.2909 11698270.

135. Freedman BD, Liu QH, Del Corno M, Collman RG. HIV-1 gp120 chemokine receptor-mediated signaling in human macrophages. Immunologic research. 2003;27(2–3):261–76. Epub 2003/07/15. doi: 10.1385/IR:27:2-3:261 12857973.

136. Maresca M, Mahfoud R, Garmy N, Kotler DP, Fantini J, Clayton F. The virotoxin model of HIV-1 enteropathy: involvement of GPR15/Bob and galactosylceramide in the cytopathic effects induced by HIV-1 gp120 in the HT-29-D4 intestinal cell line. J Biomed Sci. 2003;10(1):156–66. doi: 10.1007/bf02256007 12566994.

137. Bobardt MD, Chatterji U, Selvarajah S, Van der Schueren B, David G, Kahn B, et al. Cell-free human immunodeficiency virus type 1 transcytosis through primary genital epithelial cells. J Virol. 2007;81(1):395–405. doi: 10.1128/JVI.01303-06 17050597.

138. Howell AL, Asin SN, Yeaman GR, Wira CR. HIV-1 infection of the female reproductive tract. Current HIV/AIDS reports. 2005;2(1):35–8. Epub 2005/08/11. doi: 10.1007/s11904-996-0007-0 16091247.

139. Liu X, Zha J, Chen H, Nishitani J, Camargo P, Cole SW, et al. Human immunodeficiency virus type 1 infection and replication in normal human oral keratinocytes. J Virol. 2003;77(6):3470–6. doi: 10.1128/JVI.77.6.3470-3476.2003 12610122

140. Herrera R, Morris M, Rosbe K, Feng Z, Weinberg A, Tugizov S. Human beta-defensins 2 and -3 cointernalize with human immunodeficiency virus via heparan sulfate proteoglycans and reduce infectivity of intracellular virions in tonsil epithelial cells. Virology. 2016;487:172–87. doi: 10.1016/j.virol.2015.09.025 26539799; PubMed Central PMCID: PMC4679645.

141. Rider CC, Mulloy B. Heparin, Heparan Sulphate and the TGF-beta Cytokine Superfamily. Molecules. 2017;22(5). Epub 2017/05/05. doi: 10.3390/molecules22050713 28468283; PubMed Central PMCID: PMC6154108.

142. Barillari G, Sgadari C, Fiorelli V, Samaniego F, Colombini S, Manzari V, et al. The Tat protein of human immunodeficiency virus type-1 promotes vascular cell growth and locomotion by engaging the alpha5beta1 and alphavbeta3 integrins and by mobilizing sequestered basic fibroblast growth factor. Blood. 1999;94(2):663–72. 10397733.

143. Watson K, Edwards RJ. HIV-1-trans-activating (Tat) protein: both a target and a tool in therapeutic approaches. Biochem Pharmacol. 1999;58(10):1521–8. doi: 10.1016/s0006-2952(99)00209-9 10535742.

144. Barillari G, Sgadari C, Palladino C, Gendelman R, Caputo A, Morris CB, et al. Inflammatory cytokines synergize with the HIV-1 Tat protein to promote angiogenesis and Kaposi's sarcoma via induction of basic fibroblast growth factor and the alpha v beta 3 integrin. J Immunol. 1999;163(4):1929–35. 10438928.

145. Urbinati C, Mitola S, Tanghetti E, Kumar C, Waltenberger J, Ribatti D, et al. Integrin alphavbeta3 as a target for blocking HIV-1 Tat-induced endothelial cell activation in vitro and angiogenesis in vivo. Arterioscler Thromb Vasc Biol. 2005;25(11):2315–20. doi: 10.1161/01.ATV.0000186182.14908.7b 16166568.

146. Vogel BE, Lee SJ, Hildebrand A, Craig W, Pierschbacher MD, Wong-Staal F, et al. A novel integrin specificity exemplified by binding of the alpha v beta 5 integrin to the basic domain of the HIV Tat protein and vitronectin. J Cell Biol. 1993;121(2):461–8. doi: 10.1083/jcb.121.2.461 7682219.

147. Dwinell MB, Eckmann L, Leopard JD, Varki NM, Kagnoff MF. Chemokine receptor expression by human intestinal epithelial cells. Gastroenterology. 1999;117(2):359–67. doi: 10.1053/gast.1999.0029900359 10419917.

148. Kaplan IM, Wadia JS, Dowdy SF. Cationic TAT peptide transduction domain enters cells by macropinocytosis. Journal of controlled release: official journal of the Controlled Release Society. 2005;102(1):247–53. Epub 2005/01/18. doi: 10.1016/j.jconrel.2004.10.018 15653149.

149. Wadia JS, Stan RV, Dowdy SF. Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nat Med. 2004;10(3):310–5. Epub 2004/02/11. doi: 10.1038/nm996 14770178.

150. Mann DA, Frankel AD. Endocytosis and targeting of exogenous HIV-1 Tat protein. The EMBO journal. 1991;10(7):1733–9. Epub 1991/07/01. 2050110; PubMed Central PMCID: PMC452844.

151. Ferrari A, Pellegrini V, Arcangeli C, Fittipaldi A, Giacca M, Beltram F. Caveolae-mediated internalization of extracellular HIV-1 tat fusion proteins visualized in real time. Molecular therapy: the journal of the American Society of Gene Therapy. 2003;8(2):284–94. Epub 2003/08/09. doi: 10.1016/s1525-0016(03)00122-9 12907151.

152. Fittipaldi A, Ferrari A, Zoppe M, Arcangeli C, Pellegrini V, Beltram F, et al. Cell membrane lipid rafts mediate caveolar endocytosis of HIV-1 Tat fusion proteins. The Journal of biological chemistry. 2003;278(36):34141–9. Epub 2003/05/30. doi: 10.1074/jbc.M303045200 12773529.

153. Poggi A, Zocchi MR. HIV-1 Tat triggers TGF-beta production and NK cell apoptosis that is prevented by pertussis toxin B. Clin Dev Immunol. 2006;13(2–4):369–72. Epub 2006/12/13. doi: 10.1080/17402520600645712 17162379; PubMed Central PMCID: PMC2270756.

154. Fantini J, Maresca M, Hammache D, Yahi N, Delezay O. Glycosphingolipid (GSL) microdomains as attachment platforms for host pathogens and their toxins on intestinal epithelial cells: activation of signal transduction pathways and perturbations of intestinal absorption and secretion. Glycoconj J. 2000;17(3–4):173–9. Epub 2001/02/24. doi: 10.1023/a:1026580905156 11201788.

155. Bozou JC, Rochet N, Magnaldo I, Vincent JP, Kitabgi P. Neurotensin stimulates inositol trisphosphate-mediated calcium mobilization but not protein kinase C activation in HT29 cells. Involvement of a G-protein. Biochem J. 1989;264(3):871–8. Epub 1989/12/15. doi: 10.1042/bj2640871 2559720; PubMed Central PMCID: PMC1133666.

156. Stewart JR, O'Brian CA. Protein kinase C-{alpha} mediates epidermal growth factor receptor transactivation in human prostate cancer cells. Molecular cancer therapeutics. 2005;4(5):726–32. Epub 2005/05/18. doi: 10.1158/1535-7163.MCT-05-0013 15897236.

157. Chen X, Zhou B, Yan J, Xu B, Tai P, Li J, et al. Epidermal growth factor receptor activation by protein kinase C is necessary for FSH-induced meiotic resumption in porcine cumulus-oocyte complexes. J Endocrinol. 2008;197(2):409–19. Epub 2008/04/25. doi: 10.1677/JOE-07-0592 18434371.

158. Planes R, Serrero M, Leghmari K, BenMohamed L, Bahraoui E. HIV-1 Envelope Glycoproteins Induce the Production of TNF-alpha and IL-10 in Human Monocytes by Activating Calcium Pathway. Sci Rep. 2018;8(1):17215. Epub 2018/11/23. doi: 10.1038/s41598-018-35478-1 30464243; PubMed Central PMCID: PMC6249280.

159. Leghmari K, Bennasser Y, Tkaczuk J, Bahraoui E. HIV-1 Tat protein induces IL-10 production by an alternative TNF-alpha-independent pathway in monocytes: role of PKC-delta and p38 MAP kinase. Cell Immunol. 2008;253(1–2):45–53. Epub 2008/06/11. doi: 10.1016/j.cellimm.2008.04.015 18541226.

160. Barisoni L, Bruggeman LA, Mundel P, D'Agati VD, Klotman PE. HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy. Kidney international. 2000;58(1):173–81. Epub 2000/07/08. doi: 10.1046/j.1523-1755.2000.00152.x 10886562.

161. Schwartz EJ, Cara A, Snoeck H, Ross MD, Sunamoto M, Reiser J, et al. Human immunodeficiency virus-1 induces loss of contact inhibition in podocytes. J Am Soc Nephrol. 2001;12(8):1677–84. Epub 2001/07/20. 11461940.

162. Medapalli RK, He JC, Klotman PE. HIV-associated nephropathy: pathogenesis. Curr Opin Nephrol Hypertens. 2011;20(3):306–11. Epub 2011/03/02. doi: 10.1097/MNH.0b013e328345359a 21358326; PubMed Central PMCID: PMC3153858.

163. Bruggeman LA, Ross MD, Tanji N, Cara A, Dikman S, Gordon RE, et al. Renal epithelium is a previously unrecognized site of HIV-1 infection. J Am Soc Nephrol. 2000;11(11):2079–87. Epub 2000/10/29. 11053484.

164. Abd-El-Basset EM, Prashanth J, Ananth Lakshmi KV. Up-regulation of cytoskeletal proteins in activated microglia. Med Princ Pract. 2004;13(6):325–33. doi: 10.1159/000080469 15467307.

165. Lu TC, He JC, Wang ZH, Feng X, Fukumi-Tominaga T, Chen N, et al. HIV-1 Nef disrupts the podocyte actin cytoskeleton by interacting with diaphanous interacting protein. The Journal of biological chemistry. 2008;283(13):8173–82. Epub 2008/02/01. doi: 10.1074/jbc.M708920200 18234668; PubMed Central PMCID: PMC2276381.

166. Lan X, Wen H, Cheng K, Plagov A, Marashi Shoshtari SS, Malhotra A, et al. Hedgehog pathway plays a vital role in HIV-induced epithelial-mesenchymal transition of podocyte. Exp Cell Res. 2017;352(2):193–201. Epub 2017/02/06. doi: 10.1016/j.yexcr.2017.01.019 28159470.

167. Rosenberg AZ, Naicker S, Winkler CA, Kopp JB. HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment. Nat Rev Nephrol. 2015;11(3):150–60. Epub 2015/02/18. doi: 10.1038/nrneph.2015.9 25686569.

168. Kumar D, Konkimalla S, Yadav A, Sataranatarajan K, Kasinath BS, Chander PN, et al. HIV-associated nephropathy: role of mammalian target of rapamycin pathway. The American journal of pathology. 2010;177(2):813–21. Epub 2010/06/29. doi: 10.2353/ajpath.2010.100131 20581056; PubMed Central PMCID: PMC2913356.

169. Marras D, Bruggeman LA, Gao F, Tanji N, Mansukhani MM, Cara A, et al. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nat Med. 2002;8(5):522–6. Epub 2002/05/02. doi: 10.1038/nm0502-522 11984599.

170. Zerhouni-Layachi B, Husain M, Ross MJ, Marras D, Sunamoto M, Liu X, et al. Dual tropism of HIV-1 envelopes derived from renal tubular epithelial cells of patients with HIV-associated nephropathy. AIDS. 2006;20(4):621–4. Epub 2006/02/14. doi: 10.1097/01.aids.0000210618.68083.8e 16470129.

171. Yadav A, Vallabu S, Kumar D, Ding G, Charney DN, Chander PN, et al. HIVAN phenotype: consequence of epithelial mesenchymal transdifferentiation. American journal of physiology Renal physiology. 2010;298(3):F734–44. Epub 2009/12/18. doi: 10.1152/ajprenal.00415.2009 20015943; PubMed Central PMCID: PMC2838599.

172. Mallipattu SK, Liu R, Zhong Y, Chen EY, D'Agati V, Kaufman L, et al. Expression of HIV transgene aggravates kidney injury in diabetic mice. Kidney international. 2013. Epub 2013/01/18. doi: 10.1038/ki.2012.445 23325078.

173. Husain M, D'Agati VD, He JC, Klotman ME, Klotman PE. HIV-1 Nef induces dedifferentiation of podocytes in vivo: a characteristic feature of HIVAN. AIDS. 2005;19(17):1975–80. Epub 2005/11/02. doi: 10.1097/01.aids.0000191918.42110.27 16260903.

174. Sunamoto M, Husain M, He JC, Schwartz EJ, Klotman PE. Critical role for Nef in HIV-1-induced podocyte dedifferentiation. Kidney international. 2003;64(5):1695–701. Epub 2003/10/09. doi: 10.1046/j.1523-1755.2003.00283.x 14531802.

175. Tan R, Patni H, Tandon P, Luan L, Sharma B, Salhan D, et al. Nef interaction with actin compromises human podocyte actin cytoskeletal integrity. Experimental and molecular pathology. 2012;94(1):51–7. Epub 2012/06/23. doi: 10.1016/j.yexmp.2012.06.001 22721673; PubMed Central PMCID: PMC3463768.

176. He JC, Husain M, Sunamoto M, D'Agati VD, Klotman ME, Iyengar R, et al. Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1,2 pathways. The Journal of clinical investigation. 2004;114(5):643–51. Epub 2004/09/03. doi: 10.1172/JCI21004 15343382; PubMed Central PMCID: PMC514582.

177. Brune KA, Ferreira F, Mandke P, Chau E, Aggarwal NR, D'Alessio FR, et al. HIV Impairs Lung Epithelial Integrity and Enters the Epithelium to Promote Chronic Lung Inflammation. PLoS One. 2016;11(3):e0149679. Epub 2016/03/02. doi: 10.1371/journal.pone.0149679 26930653; PubMed Central PMCID: PMC4773117.

178. Chung CY, Alden SL, Funderburg NT, Fu P, Levine AD. Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals. PLoS Pathog. 2014;10(6):e1004198. Epub 2014/06/27. doi: 10.1371/journal.ppat.1004198 24968145; PubMed Central PMCID: PMC4072797.

179. Munawwar A, Singh S. Human Herpesviruses as Copathogens of HIV Infection, Their Role in HIV Transmission, and Disease Progression. J Lab Physicians. 2016;8(1):5–18. Epub 2016/03/26. doi: 10.4103/0974-2727.176228 27013807; PubMed Central PMCID: PMC4785766.

180. Liberto MC, Zicca E, Pavia G, Quirino A, Marascio N, Torti C, et al. Virological Mechanisms in the Coinfection between HIV and HCV. Mediators Inflamm. 2015;2015:320532. Epub 2015/10/27. doi: 10.1155/2015/320532 26494946; PubMed Central PMCID: PMC4606210.

181. Singh KP, Crane M, Audsley J, Avihingsanon A, Sasadeusz J, Lewin SR. HIV-hepatitis B virus coinfection: epidemiology, pathogenesis, and treatment. AIDS. 2017;31(15):2035–52. Epub 2017/07/12. doi: 10.1097/QAD.0000000000001574 28692539; PubMed Central PMCID: PMC5661989.

182. Groeger S, Meyle J. Oral Mucosal Epithelial Cells. Front Immunol. 2019;10:208. Epub 2019/03/07. doi: 10.3389/fimmu.2019.00208 30837987; PubMed Central PMCID: PMC6383680.

183. De Tomasi JB, Opata MM, Mowa CN. Immunity in the Cervix: Interphase between Immune and Cervical Epithelial Cells. J Immunol Res. 2019;2019:7693183. Epub 2019/05/31. doi: 10.1155/2019/7693183 31143785; PubMed Central PMCID: PMC6501150.

184. Berth S, Caicedo HH, Sarma T, Morfini G, Brady ST. Internalization and axonal transport of the HIV glycoprotein gp120. ASN Neuro. 2015;7(1). Epub 2015/02/01. doi: 10.1177/1759091414568186 25636314; PubMed Central PMCID: PMC4720180.

185. Pandhare J, Dash S, Jones B, Villalta F, Dash C. A Novel Role of Proline Oxidase in HIV-1 Envelope Glycoprotein-induced Neuronal Autophagy. J Biol Chem. 2015;290(42):25439–51. Epub 2015/09/04. doi: 10.1074/jbc.M115.652776 26330555; PubMed Central PMCID: PMC4646191.

186. Bai L, Zhang Z, Zhang H, Li X, Yu Q, Lin H, et al. HIV-1 Tat protein alter the tight junction integrity and function of retinal pigment epithelium: an in vitro study. BMC Infect Dis. 2008;8:77. doi: 10.1186/1471-2334-8-77 18538010.


Článek vyšel v časopise

PLOS One


2019 Číslo 12