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. 1998 Oct;74(5):349–353. doi: 10.1136/sti.74.5.349

Tissue specific HPV expression and downregulation of local immune responses in condylomas from HIV seropositive individuals

I Arany, T Evans, S K Tyring
PMCID: PMC1758139  PMID: 10195031

Abstract

OBJECTIVE: To study the effect of tissue specific human papillomavirus (HPV) expression and its effect on local immunity in condylomas from HIV positive individuals. METHODS: Biopsy specimens of eight penile and eight perianal condylomas from HIV seropositive individuals were analysed. Expression of viral genes (HIV-tat and HPV E7 and L1) was determined by RT-PCR. The status of local immunity also was determined by RT-PCR by measuring CD4, CD8, CD16, CD1a, HLA-DR, and HLA-B7 mRNA levels in the tissues. Differentiation was determined by measuring involucrin, keratinocyte transglutaminase, as well as cytokeratins 10, 16, and 17. Proliferation markers such as PCNA and c-myc were also determined. RESULTS: The transcription pattern of HPV in perianal condylomas, which preferentially expressed the early (E7) gene, was different from that of penile condylomas, which primarily expressed the late (L1) gene. This transcription pattern is in good correlation with the keratinisation and differentiation patterns of the two epithelia: perianal biopsies preferentially expressed K16 and K17 while penile warts mainly expressed K10, markers of parakeratotic and orthokeratotic epithelia, respectively. Perianal biopsies also showed a higher degree of proliferation (PCNA and c-myc). Interestingly, transcription of HIV-tat was also higher in perianal than in penile biopsies. A high degree of local immunodeficiency was observed in perianal biopsies--that is, levels of CD4, CD16, and CD1a mRNAs were significantly lower. A negative correlation between CD1a (Langerhans cells) levels and HPV E7 levels was established. HPV E7 levels positively correlated with HIV-tat levels. Perianal tissues demonstrated more CD1a depression and tat associated HPV upregulation. CONCLUSION: HIV influences the expression of HPV genes resulting in local immunosuppression that might lead to an inappropriate immune surveillance of viral infection. Also, tissue type is an important factor in controlling viral transcription in a differentiation dependent manner. These findings may explain the higher rate of dysplasia and neoplasia in the perianal area. 




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Selected References

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  1. Altmann A., Jochmus I., Rösl F. Intra- and extracellular control mechanisms of human papillomavirus infection. Intervirology. 1994;37(3-4):180–188. doi: 10.1159/000150376. [DOI] [PubMed] [Google Scholar]
  2. Arany I., Brysk M. M., Brysk H., Tyring S. K. Response to interferon treatment decreases with epidermal dedifferentiation in condylomas. Antiviral Res. 1996 Aug;32(1):19–26. doi: 10.1016/0166-3542(95)00970-1. [DOI] [PubMed] [Google Scholar]
  3. Arany I., Rady P., Tyring S. K. Alterations in cytokine/antioncogene expression in skin lesions caused by "low-risk" types of human papillomaviruses. Viral Immunol. 1993 Winter;6(4):255–265. doi: 10.1089/vim.1993.6.255. [DOI] [PubMed] [Google Scholar]
  4. Arany I., Tyring S. K. Activation of local cell-mediated immunity in interferon-responsive patients with human papillomavirus-associated lesions. J Interferon Cytokine Res. 1996 Jun;16(6):453–460. doi: 10.1089/jir.1996.16.453. [DOI] [PubMed] [Google Scholar]
  5. Arany I., Tyring S. K. Status of local cellular immunity in interferon-responsive and -nonresponsive human papillomavirus-associated lesions. Sex Transm Dis. 1996 Nov-Dec;23(6):475–480. doi: 10.1097/00007435-199611000-00007. [DOI] [PubMed] [Google Scholar]
  6. Arany I., Tyring S. K. Systemic immunosuppression by HIV infection influences HPV transcription and thus local immune responses in condyloma acuminatum. Int J STD AIDS. 1998 May;9(5):268–271. doi: 10.1258/0956462981922197. [DOI] [PubMed] [Google Scholar]
  7. Barker J. N., Goodlad J. R., Ross E. L., Yu C. C., Groves R. W., MacDonald D. M. Increased epidermal cell proliferation in normal human skin in vivo following local administration of interferon-gamma. Am J Pathol. 1993 Apr;142(4):1091–1097. [PMC free article] [PubMed] [Google Scholar]
  8. Beckmann A. M., Sherman K. J., Myerson D., Daling J. R., McDougall J. K., Galloway D. A. Comparative virologic studies of condylomata acuminata reveal a lack of dual infections with human papillomaviruses. J Infect Dis. 1991 Feb;163(2):393–396. doi: 10.1093/infdis/163.2.393. [DOI] [PubMed] [Google Scholar]
  9. Blauvelt A., Katz S. I. The skin as target, vector, and effector organ in human immunodeficiency virus disease. J Invest Dermatol. 1995 Jul;105(1 Suppl):122S–126S. doi: 10.1111/1523-1747.ep12316662. [DOI] [PubMed] [Google Scholar]
  10. Braun L. Role of human immunodeficiency virus infection in the pathogenesis of human papillomavirus-associated cervical neoplasia. Am J Pathol. 1994 Feb;144(2):209–214. [PMC free article] [PubMed] [Google Scholar]
  11. Breese P. L., Judson F. N., Penley K. A., Douglas J. M., Jr Anal human papillomavirus infection among homosexual and bisexual men: prevalence of type-specific infection and association with human immunodeficiency virus. Sex Transm Dis. 1995 Jan-Feb;22(1):7–14. doi: 10.1097/00007435-199501000-00002. [DOI] [PubMed] [Google Scholar]
  12. Brown D. R., Bryan J. T., Cramer H., Katz B. P., Handy V., Fife K. H. Detection of multiple human papillomavirus types in condylomata acuminata from immunosuppressed patients. J Infect Dis. 1994 Oct;170(4):759–765. doi: 10.1093/infdis/170.4.759. [DOI] [PubMed] [Google Scholar]
  13. Brown D. R., Fife K. H. Human papillomavirus infections of the genital tract. Med Clin North Am. 1990 Nov;74(6):1455–1485. doi: 10.1016/s0025-7125(16)30490-4. [DOI] [PubMed] [Google Scholar]
  14. Caussy D., Goedert J. J., Palefsky J., Gonzales J., Rabkin C. S., DiGioia R. A., Sanchez W. C., Grossman R. J., Colclough G., Wiktor S. Z. Interaction of human immunodeficiency and papilloma viruses: association with anal epithelial abnormality in homosexual men. Int J Cancer. 1990 Aug 15;46(2):214–219. doi: 10.1002/ijc.2910460212. [DOI] [PubMed] [Google Scholar]
  15. Chang H.-K., Gallo R.C., Ensoli B. Regulation of Cellular Gene Expression and Function by the Human Immunodeficiency Virus Type 1 Tat Protein. J Biomed Sci. 1995 Aug;2(3):189–202. doi: 10.1007/BF02253380. [DOI] [PubMed] [Google Scholar]
  16. Chirgwin K. D., Feldman J., Augenbraun M., Landesman S., Minkoff H. Incidence of venereal warts in human immunodeficiency virus-infected and uninfected women. J Infect Dis. 1995 Jul;172(1):235–238. doi: 10.1093/infdis/172.1.235. [DOI] [PubMed] [Google Scholar]
  17. Coleman N., Birley H. D., Renton A. M., Hanna N. F., Ryait B. K., Byrne M., Taylor-Robinson D., Stanley M. A. Immunological events in regressing genital warts. Am J Clin Pathol. 1994 Dec;102(6):768–774. doi: 10.1093/ajcp/102.6.768. [DOI] [PubMed] [Google Scholar]
  18. Connor M. E., Stern P. L. Loss of MHC class-I expression in cervical carcinomas. Int J Cancer. 1990 Dec 15;46(6):1029–1034. doi: 10.1002/ijc.2910460614. [DOI] [PubMed] [Google Scholar]
  19. Feingold A. R., Vermund S. H., Burk R. D., Kelley K. F., Schrager L. K., Schreiber K., Munk G., Friedland G. H., Klein R. S. Cervical cytologic abnormalities and papillomavirus in women infected with human immunodeficiency virus. J Acquir Immune Defic Syndr. 1990;3(9):896–903. [PubMed] [Google Scholar]
  20. Fenger C. Histology of the anal canal. Am J Surg Pathol. 1988 Jan;12(1):41–55. doi: 10.1097/00000478-198801000-00006. [DOI] [PubMed] [Google Scholar]
  21. Fuchs E. Epidermal differentiation: the bare essentials. J Cell Biol. 1990 Dec;111(6 Pt 2):2807–2814. doi: 10.1083/jcb.111.6.2807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hughes R. G., Norval M., Howie S. E. Expression of major histocompatibility class II antigens by Langerhans' cells in cervical intraepithelial neoplasia. J Clin Pathol. 1988 Mar;41(3):253–259. doi: 10.1136/jcp.41.3.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hussain L. A., Lehner T. Comparative investigation of Langerhans' cells and potential receptors for HIV in oral, genitourinary and rectal epithelia. Immunology. 1995 Jul;85(3):475–484. [PMC free article] [PubMed] [Google Scholar]
  24. Iftner T., Oft M., Böhm S., Wilczynski S. P., Pfister H. Transcription of the E6 and E7 genes of human papillomavirus type 6 in anogenital condylomata is restricted to undifferentiated cell layers of the epithelium. J Virol. 1992 Aug;66(8):4639–4646. doi: 10.1128/jvi.66.8.4639-4646.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Johnson J. C., Burnett A. F., Willet G. D., Young M. A., Doniger J. High frequency of latent and clinical human papillomavirus cervical infections in immunocompromised human immunodeficiency virus-infected women. Obstet Gynecol. 1992 Mar;79(3):321–327. doi: 10.1097/00006250-199203000-00001. [DOI] [PubMed] [Google Scholar]
  26. Kim K. H., Schwartz F., Fuchs E. Differences in keratin synthesis between normal epithelial cells and squamous cell carcinomas are mediated by vitamin A. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4280–4284. doi: 10.1073/pnas.81.14.4280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Leader M., Collins M., Patel J., Henry K. Vimentin: an evaluation of its role as a tumour marker. Histopathology. 1987 Jan;11(1):63–72. doi: 10.1111/j.1365-2559.1987.tb02609.x. [DOI] [PubMed] [Google Scholar]
  28. Lehtinen M., Rantala I., Toivonen A., Luoto H., Aine R., Lauslahti K., Ylä-Outinen A., Romppanen U., Paavonen J. Depletion of Langerhans cells in cervical HPV infection is associated with replication of the virus. APMIS. 1993 Nov;101(11):833–837. doi: 10.1111/j.1699-0463.1993.tb00188.x. [DOI] [PubMed] [Google Scholar]
  29. Matorras R., Ariceta J. M., Rementeria A., Corral J., Gutierrez de Terán G., Diez J., Montoya F., Rodriguez-Escudero F. J. Human immunodeficiency virus-induced immunosuppression: a risk factor for human papillomavirus infection. Am J Obstet Gynecol. 1991 Jan;164(1 Pt 1):42–44. doi: 10.1016/0002-9378(91)90620-7. [DOI] [PubMed] [Google Scholar]
  30. McFadden G., Kane K. How DNA viruses perturb functional MHC expression to alter immune recognition. Adv Cancer Res. 1994;63:117–209. doi: 10.1016/s0065-230x(08)60400-5. [DOI] [PubMed] [Google Scholar]
  31. Melbye M., Palefsky J., Gonzales J., Ryder L. P., Nielsen H., Bergmann O., Pindborg J., Biggar R. J. Immune status as a determinant of human papillomavirus detection and its association with anal epithelial abnormalities. Int J Cancer. 1990 Aug 15;46(2):203–206. doi: 10.1002/ijc.2910460210. [DOI] [PubMed] [Google Scholar]
  32. Memar O. M., Arany I., Tyring S. K. Skin-associated lymphoid tissue in human immunodeficiency virus-1, human papillomavirus, and herpes simplex virus infections. J Invest Dermatol. 1995 Jul;105(1 Suppl):99S–104S. doi: 10.1111/1523-1747.ep12316241. [DOI] [PubMed] [Google Scholar]
  33. Moll R., Franke W. W., Schiller D. L., Geiger B., Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982 Nov;31(1):11–24. doi: 10.1016/0092-8674(82)90400-7. [DOI] [PubMed] [Google Scholar]
  34. Müller H., Weier S., Kojouharoff G., Grez M., Berger S., Kappus R., Shah P. M., Stutte H. J., Schmidts H. L. Distribution and infection of Langerhans cells in the skin of HIV-infected healthy subjects and AIDS patients. Res Virol. 1993 Jan-Feb;144(1):59–67. doi: 10.1016/s0923-2516(06)80013-0. [DOI] [PubMed] [Google Scholar]
  35. Münger K., Phelps W. C. The human papillomavirus E7 protein as a transforming and transactivating factor. Biochim Biophys Acta. 1993 May 25;1155(1):111–123. doi: 10.1016/0304-419x(93)90025-8. [DOI] [PubMed] [Google Scholar]
  36. Rady P. L., Arany I., Hughes T. K., Tyring S. K. Type-specific primer-mediated direct sequencing of consensus primer-generated PCR amplicons of human papilloma viruses: a new approach for the simultaneous detection of multiple viral type infections. J Virol Methods. 1995 Jun;53(2-3):245–254. doi: 10.1016/0166-0934(95)00029-t. [DOI] [PubMed] [Google Scholar]
  37. Resnick R. M., Cornelissen M. T., Wright D. K., Eichinger G. H., Fox H. S., ter Schegget J., Manos M. M. Detection and typing of human papillomavirus in archival cervical cancer specimens by DNA amplification with consensus primers. J Natl Cancer Inst. 1990 Sep 19;82(18):1477–1484. doi: 10.1093/jnci/82.18.1477. [DOI] [PubMed] [Google Scholar]
  38. Roberts J. M. Turning DNA replication on and off. Curr Opin Cell Biol. 1993 Apr;5(2):201–206. doi: 10.1016/0955-0674(93)90103-w. [DOI] [PubMed] [Google Scholar]
  39. Schneider A. Pathogenesis of genital HPV infection. Genitourin Med. 1993 Jun;69(3):165–173. doi: 10.1136/sti.69.3.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Schäfer A., Friedmann W., Mielke M., Schwartländer B., Koch M. A. The increased frequency of cervical dysplasia-neoplasia in women infected with the human immunodeficiency virus is related to the degree of immunosuppression. Am J Obstet Gynecol. 1991 Feb;164(2):593–599. doi: 10.1016/s0002-9378(11)80029-3. [DOI] [PubMed] [Google Scholar]
  41. Stoler M. H., Wolinsky S. M., Whitbeck A., Broker T. R., Chow L. T. Differentiation-linked human papillomavirus types 6 and 11 transcription in genital condylomata revealed by in situ hybridization with message-specific RNA probes. Virology. 1989 Sep;172(1):331–340. doi: 10.1016/0042-6822(89)90135-9. [DOI] [PubMed] [Google Scholar]
  42. Tornesello M. L., Buonaguro F. M., Beth-Giraldo E., Giraldo G. Human immunodeficiency virus type 1 tat gene enhances human papillomavirus early gene expression. Intervirology. 1993;36(2):57–64. doi: 10.1159/000150322. [DOI] [PubMed] [Google Scholar]
  43. Vermund S. H., Kelley K. F., Klein R. S., Feingold A. R., Schreiber K., Munk G., Burk R. D. High risk of human papillomavirus infection and cervical squamous intraepithelial lesions among women with symptomatic human immunodeficiency virus infection. Am J Obstet Gynecol. 1991 Aug;165(2):392–400. doi: 10.1016/0002-9378(91)90101-v. [DOI] [PubMed] [Google Scholar]
  44. Vernon S. D., Hart C. E., Reeves W. C., Icenogle J. P. The HIV-1 tat protein enhances E2-dependent human papillomavirus 16 transcription. Virus Res. 1993 Feb;27(2):133–145. doi: 10.1016/0168-1702(93)90077-z. [DOI] [PubMed] [Google Scholar]
  45. Viac J., Chardonnet Y., Euvrard S., Chignol M. C., Thivolet J. Langerhans cells, inflammation markers and human papillomavirus infections in benign and malignant epithelial tumors from transplant recipients. J Dermatol. 1992 Feb;19(2):67–77. doi: 10.1111/j.1346-8138.1992.tb03183.x. [DOI] [PubMed] [Google Scholar]
  46. Viac J., Soler C., Chardonnet Y., Euvrard S., Schmitt D. Expression of immune associated surface antigens of keratinocytes in human papillomavirus-derived lesions. Immunobiology. 1993 Aug;188(4-5):392–402. doi: 10.1016/S0171-2985(11)80222-6. [DOI] [PubMed] [Google Scholar]
  47. Waga S., Hannon G. J., Beach D., Stillman B. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature. 1994 Jun 16;369(6481):574–578. doi: 10.1038/369574a0. [DOI] [PubMed] [Google Scholar]
  48. Williams G. R., Talbot I. C., Northover J. M., Leigh I. M. Keratin expression in the normal anal canal. Histopathology. 1995 Jan;26(1):39–44. doi: 10.1111/j.1365-2559.1995.tb00618.x. [DOI] [PubMed] [Google Scholar]
  49. Woodworth C. D., Simpson S. Comparative lymphokine secretion by cultured normal human cervical keratinocytes, papillomavirus-immortalized, and carcinoma cell lines. Am J Pathol. 1993 May;142(5):1544–1555. [PMC free article] [PubMed] [Google Scholar]
  50. zur Hausen H. Papillomavirus infections--a major cause of human cancers. Biochim Biophys Acta. 1996 Oct 9;1288(2):F55–F78. doi: 10.1016/0304-419x(96)00020-0. [DOI] [PubMed] [Google Scholar]

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