Presence of CD8+ T cells in the ectocervical mucosa correlates with genital viral shedding in HIV-infected women despite a low prevalence of HIV RNA-expressing cells in the tissue

Journal of Immunology

Volumn 192, Issue 8, 2014, Pages 3947-3957

  Gibbs, Anna ^a   Hirbod, Taha ^a   Li, Qingsheng ^b   Bohman, Karin ^a   Ball, Terry B ^c,d   Plummer, Francis A ^c,d   Kaul, Rupert ^e   Kimani, Joshua ^f   Broliden, Kristina ^a   Tjernlund, Annelie ^a  

^a KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^b UNIVERSITY OF NEBRASKA LINCOLN   (United States)

^c UNIVERSITY OF MANITOBA   (Canada)

^d PUBLIC HEALTH AGENCY OF CANADA   (Canada)

^e UNIVERSITY OF TORONTO   (Canada)

^f UNIVERSITY OF NAIROBI   (Kenya)

Author keywords

[No Author keywords available]

Indexed keywords

ADULT; ANTIGENS, CD3; ANTIGENS, CD8; CD8-POSITIVE T-LYMPHOCYTES; CERVIX UTERI; FEMALE; GENE EXPRESSION REGULATION; GENE EXPRESSION REGULATION, VIRAL; HIV INFECTIONS; HIV-1; HLA-DR ANTIGENS; HUMANS; MIDDLE AGED; MUCOUS MEMBRANE; PHENOTYPE; RISK FACTORS; RNA, VIRAL; SEX WORKERS; T-LYMPHOCYTE SUBSETS; VIRAL LOAD; VIRUS SHEDDING; YOUNG ADULT;

EID: 84898632823     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1302826     Document Type: Article

References (56)

1. Nkwanyana, N. N., P. P. Gumbi, L. Roberts, L. Denny, W. Hanekom, A. Soares, B. Allan, A. L. Williamson, D. Coetzee, A. J. Olivier, et al. 2009. Impact of human immunodeficiency virus 1 infection and inflammation on the composition and yield of cervical mononuclear cells in the female genital tract. Immunology 128(1 Suppl.): e746-e757.
2. Musey, L., Y. Hu, L. Eckert, M. Christensen, T. Karchmer, and M. J. McElrath. 1997. HIV-1 induces cytotoxic T lymphocytes in the cervix of infected women. J. Exp. Med. 185: 293-303.
3. Bere, A., L. Denny, P. Naicker, W. A. Burgers, and J. A. Passmore. 2013. HIVspecific T-cell responses detected in the genital tract of chronically HIV-infected women are largely monofunctional. Immunology 139: 342-351.
4. Gumbi, P. P., S. Z. Jaumdally, A. L. Salkinder, W. A. Burgers, N. N. Mkhize, W. Hanekom, D. Coetzee, A. Williamson, and J. S. Passmore. 2011. CD4 T cell depletion at the cervix during HIV infection is associated with accumulation of terminally differentiated T cells. J. Virol. 85: 13333-13341.
5. Olaitan, A., M. A. Johnson, A. MacLean, and L. W. Poulter. 1996. The distribution of immunocompetent cells in the genital tract of HIV-positive women. AIDS 10: 759-764.
6. Bebell, L. M., J. A. Passmore, C. Williamson, K. Mlisana, I. Iriogbe, F. van Loggerenberg, Q. A. Karim, and S. A. Karim. 2008. Relationship between levels of inflammatory cytokines in the genital tract and CD4+ cell counts in women with acute HIV-1 infection. J. Infect. Dis. 198: 710-714.
7. Roberts, L., J. A. Passmore, K. Mlisana, C. Williamson, F. Little, L. M. Bebell, G. Walzl, M. R. Abrahams, Z. Woodman, Q. Abdool Karim, and S. S. Abdool Karim. 2012. Genital tract inflammation during early HIV-1 infection predicts higher plasma viral load set point in women. J. Infect. Dis. 205: 194-203.
8. Southern, P. J. 2013. Missing out on the biology of heterosexual HIV-1 transmission. Trends Microbiol. 21: 245-252.
9. Hirbod, T., J. Kimani, A. Tjernlund, J. Cheruiyot, A. Petrova, T. B. Ball, N. Mugo, W. Jaoko, F. A. Plummer, R. Kaul, and K. Broliden. 2013. Stable CD4 expression and local immune activation in the ectocervical mucosa of HIV-infected women. J. Immunol. 191: 3948-3954.
10. Quinn, T. C., M. J. Wawer, N. Sewankambo, D. Serwadda, C. Li, F. Wabwire-Mangen, M. O. Meehan, T. Lutalo, and R. H. Gray; Rakai Project Study Group. 2000. Viral load and heterosexual transmission of human immunodeficiency virus type 1. N. Engl. J. Med. 342: 921-929.
11. Cu-Uvin, S., B. Snyder, J. I. Harwell, J. Hogan, C. Chibwesha, D. Hanley, J. Ingersoll, J. Kurpewski, K. H. Mayer, and A. M. Caliendo. 2006. Association between paired plasma and cervicovaginal lavage fluid HIV-1 RNA levels during 36 months. J. Acquir. Immune Defic. Syndr. 42: 584-587.
12. Kovacs, A., S. S. Wasserman, D. Burns, D. J. Wright, J. Cohn, A. Landay, K. Weber, M. Cohen, A. Levine, H. Minkoff, et al; DATRI Study Group; WIHS Study Group. 2001. Determinants of HIV-1 shedding in the genital tract of women. Lancet 358: 1593-1601.
13. Mostad, S. B. 1998. Prevalence and correlates of HIV type 1 shedding in the female genital tract. AIDS Res. Hum. Retroviruses 14(Suppl. 1): S11-S15.
14. Baeten, J. M., E. Kahle, J. R. Lingappa, R. W. Coombs, S. Delany-Moretlwe, E. Nakku-Joloba, N. R. Mugo, A. Wald, L. Corey, D. Donnell, et al; Partners in Prevention HSV/HIV Transmission Study Team. 2011. Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission. Sci. Transl. Med. 3: 77ra29.
15. Baeten, J. M., and J. Overbaugh. 2003. Measuring the infectiousness of persons with HIV-1: opportunities for preventing sexual HIV-1 transmission. Curr. HIV Res. 1: 69-86.
16. Blish, C. A., R. S. McClelland, B. A. Richardson, W. Jaoko, K. Mandaliya, J. M. Baeten, and J. Overbaugh. 2012. Genital Inflammation Predicts HIV-1 Shedding Independent of Plasma Viral Load and Systemic Inflammation. J. Acquir. Immune Defic. Syndr. 61: 436-440.
17. Mukura, L. R., M. Ghosh, J. V. Fahey, S. Cu-Uvin, and C. R. Wira. 2012. Genital tract viral load in HIV Type 1-positive women correlates with specific cytokine levels in cervical-vaginal secretions but is not a determinant of infectious virus or anti-HIV activity. AIDS Res. Hum. Retroviruses 28: 1533-1539.
18. Anderson, B. L., C. C. Wang, A. K. Delong, T. Liu, E. M. Kojic, J. Kurpewski, J. Ingersoll, K. Mayer, A. M. Caliendo, and S. Cu-Uvin. 2008. Genital tract leukocytes and shedding of genital HIV type 1 RNA. Clin. Infect. Dis. 47: 1216-1221.
19. Baeten, J. M., L. B. Strick, A. Lucchetti, W. L. Whittington, J. Sanchez, R. W. Coombs, A. Magaret, A. Wald, L. Corey, and C. Celum. 2008. Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial. J. Infect. Dis. 198: 1804-1808.
20. Clark, R. A., K. P. Theall, A. M. Amedee, and P. J. Kissinger. 2007. Frequent douching and clinical outcomes among HIV-infected women. Sex. Transm. Dis. 34: 985-990.
21. Clemetson, D. B., G. B. Moss, D. M. Willerford, M. Hensel, W. Emonyi, K. K. Holmes, F. Plummer, J. Ndinya-Achola, P. L. Roberts, S. Hillier, et al. 1993. Detection of HIV DNA in cervical and vaginal secretions. Prevalence and correlates among women in Nairobi, Kenya. JAMA 269: 2860-2864.
22. Heffron, R., D. Donnell, H. Rees, C. Celum, N. Mugo, E. Were, G. de Bruyn, E. Nakku-Joloba, K. Ngure, J. Kiarie, et al; Partners in Prevention HSV/HIV Transmission Study Team. 2012. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect. Dis. 12: 19-26.
23. Johnson, L. F., and D. A. Lewis. 2008. The effect of genital tract infections on HIV-1 shedding in the genital tract: a systematic review and meta-analysis. Sex. Transm. Dis. 35: 946-959.
24. Mcclelland, R. S., C. C. Wang, K. Mandaliya, J. Overbaugh, M. T. Reiner, D. D. Panteleeff, L. Lavreys, J. Ndinya-Achola, J. J. Bwayo, and J. K. Kreiss. 2001. Treatment of cervicitis is associated with decreased cervical shedding of HIV-1. AIDS 15: 105-110.
25. McClelland, R. S., C. C. Wang, J. Overbaugh, B. A. Richardson, L. Corey, R. L. Ashley, K. Mandaliya, J. Ndinya-Achola, J. J. Bwayo, and J. K. Kreiss. 2002. Association between cervical shedding of herpes simplex virus and HIV-1. AIDS 16: 2425-2430.
26. Nagot, N., A. Ouédraogo, V. Foulongne, I. Konaté, H. A. Weiss, L. Vergne, M. C. Defer, D. Djagbaré, A. Sanon, J. B. Andonaba, et al; ANRS 1285 Study Group. 2007. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N. Engl. J. Med. 356: 790-799.
27. Rodriguez-Garcia, M., M. V. Patel, and C. R. Wira. 2013. Innate and adaptive anti-HIV immune responses in the female reproductive tract. J. Reprod. Immunol. 97: 74-84.
28. Wang, C. C., R. S. McClelland, J. Overbaugh, M. Reilly, D. D. Panteleeff, K. Mandaliya, B. Chohan, L. Lavreys, J. Ndinya-Achola, and J. K. Kreiss. 2004. The effect of hormonal contraception on genital tract shedding of HIV-1. AIDS 18: 205-209.
29. Cu-Uvin, S., A. K. DeLong, K. K. Venkatesh, J. W. Hogan, J. Ingersoll, J. Kurpewski, M. P. De Pasquale, R. D'Aquila, and A. M. Caliendo. 2010. Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load. AIDS 24: 2489-2497.
30. Dornadula, G., H. Zhang, B. VanUitert, J. Stern, L. Livornese, Jr., M. J. Ingerman, J. Witek, R. J. Kedanis, J. Natkin, J. DeSimone, and R. J. Pomerantz. 1999. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA 282: 1627-1632.
31. Coombs, R.W., P. S. Reichelderfer, and A. L. Landay. 2003. Recent observations on HIV type-1 infection in the genital tract of men and women. AIDS 17: 455-480.
32. Iqbal, S. M., T. B. Ball, J. Kimani, P. Kiama, P. Thottingal, J. E. Embree, K. R. Fowke, and F. A. Plummer. 2005. Elevated T cell counts and RANTES expression in the genital mucosa of HIV-1-resistant Kenyan commercial sex workers. J. Infect. Dis. 192: 728-738.
33. Behbahani, H., L. Walther-Jallow, E. Klareskog, L. Baum, A. L. French, B. K. Patterson, P. Garcia, A. L. Spetz, A. Landay, and J. Andersson. 2007. Proinflammatory and type 1 cytokine expression in cervical mucosa during HIV-1 and human papillomavirus infection. J. Acquir. Immune Defic. Syndr. 45: 9-19.
34. Nuovo, G. J., A. Forde, P. MacConnell, and R. Fahrenwald. 1993. In situ detection of PCR-amplified HIV-1 nucleic acids and tumor necrosis factor cDNA in cervical tissues. Am. J. Pathol. 143: 40-48.
35. Olaitan, A., M. A. Johnson, W. M. Reid, and L. W. Poulter. 1998. Changes to the cytokine microenvironment in the genital tract mucosa of HIV+ women. Clin. Exp. Immunol. 112: 100-104.
36. Pomerantz, R. J., S. M. de la Monte, S. P. Donegan, T. R. Rota, M. W. Vogt, D. E. Craven, and M. S. Hirsch. 1988. Human immunodeficiency virus (HIV) infection of the uterine cervix. Ann. Intern. Med. 108: 321-327.
37. Embree, J. E., S. Njenga, P. Datta, N. J. Nagelkerke, J. O. Ndinya-Achola, Z. Mohammed, S. Ramdahin, J. J. Bwayo, and F. A. Plummer. 2000. Risk factors for postnatal mother-child transmission of HIV-1. AIDS 14: 2535-2541.
38. Fowke, K. R., N. J. Nagelkerke, J. Kimani, J. N. Simonsen, A. O. Anzala, J. J. Bwayo, K. S. MacDonald, E. N. Ngugi, and F. A. Plummer. 1996. Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya. Lancet 348: 1347-1351.
39. Hasselrot, K., J. Cheruiyot, J. Kimani, T. B. Ball, R. Kaul, and T. Hirbod. 2012. Feasibility and safety of cervical biopsy sampling for mucosal immune studies in female sex workers from Nairobi, Kenya. PLoS ONE 7: e47570.
40. Li, Q., L. Duan, J. D. Estes, Z. M. Ma, T. Rourke, Y. Wang, C. Reilly, J. Carlis, C. J. Miller, and A. T. Haase. 2005. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434: 1148-1152.
41. Li, Q., T. Schacker, J. Carlis, G. Beilman, P. Nguyen, and A. T. Haase. 2004. Functional genomic analysis of the response of HIV-1-infected lymphatic tissue to antiretroviral therapy. J. Infect. Dis. 189: 572-582.
42. Brismar Wendel, S., T. Kaldensjö, P. Peterson, S. Andersson, K. Broliden, and T. Hirbod. 2010. Slumbering mucosal immune response in the cervix of human papillomavirus DNA-positive and-negative women. Int. J. Oncol. 37: 1565-1573.
43. Andersson, J., T. E. Fehniger, B. K. Patterson, J. Pottage, M. Agnoli, P. Jones, H. Behbahani, and A. Landay. 1998. Early reduction of immune activation in lymphoid tissue following highly active HIV therapy. AIDS 12: F123-F129.
44. Hirbod, T., R. C. Bailey, K. Agot, S. Moses, J. Ndinya-Achola, R. Murugu, J. Andersson, J. Nilsson, and K. Broliden. 2010. Abundant expression of HIV target cells and C-type lectin receptors in the foreskin tissue of young Kenyan men. Am. J. Pathol. 176: 2798-2805.
45. Bjork, L., T. E. Fehniger, U. Andersson, and J. Andersson. 1996. Computerized assessment of production of multiple human cytokines at the single-cell level using image analysis. J. Leukoc. Biol. 59: 287-295.
46. Masopust, D., and J. M. Schenkel. 2013. The integration of T cell migration, differentiation and function. Nat. Rev. Immunol. 13: 309-320.
47. Mueller, S. N., T. Gebhardt, F. R. Carbone, and W. R. Heath. 2013. Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 31: 137-161.
48. Jaspan, H. B., L. Liebenberg, W. Hanekom, W. Burgers, D. Coetzee, A. L.Williamson, F. Little, L. Myer, R. W. Coombs, D. Sodora, and J. A. Passmore. 2011. Immune activation in the female genital tract during HIV infection predicts mucosal CD4 depletion and HIV shedding. J. Infect. Dis. 204: 1550-1556.
49. Miedema, F., M. D. Hazenberg, K. Tesselaar, D. van Baarle, R. J. de Boer, and J. A. Borghans. 2013. Immune Activation and Collateral Damage in AIDS Pathogenesis. Front. Immunol. 4: 298.
50. Abdulhaqq, S. A., M. I. Martinez, G. Kang, A. S. Foulkes, I. V. Rodriguez, S. M. Nichols, M. Hunter, C. A. Sariol, L. A. Ruiz, B. N. Ross, et al. 2013. Serial cervicovaginal exposures with replication-deficient sivsm induce higher dendritic cell (pdc) and cd4+ t-cell infiltrates not associated with prevention but a more severe sivmac251 infection of rhesus macaques. J. Acquir. Immune Defic. Syndr. In press.
51. Li, Q., J. D. Estes, P. M. Schlievert, L. Duan, A. J. Brosnahan, P. J. Southern, C. S. Reilly, M. L. Peterson, N. Schultz-Darken, K. G. Brunner, et al. 2009. Glycerol monolaurate prevents mucosal SIV transmission. Nature 458: 1034-1038.
52. Cohn, M. A., S. S. Frankel, S. Rugpao, M. A. Young, G. Willett, S. Tovanabutra, C. Khamboonruang, T. VanCott, L. Bhoopat, S. Barrick, et al. 2001. Chronic inflammation with increased human immunodeficiency virus (HIV) RNA expression in the vaginal epithelium of HIV-infected Thai women. J. Infect. Dis. 184: 410-417.
53. Haase, A. T., K. Henry, M. Zupancic, G. Sedgewick, R. A. Faust, H. Melroe, W. Cavert, K. Gebhard, K. Staskus, Z. Q. Zhang, et al. 1996. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274: 985-989.
54. Card, C. M., P. J. McLaren, C. Wachihi, J. Kimani, F. A. Plummer, and K. R. Fowke. 2009. Decreased immune activation in resistance to HIV-1 infection is associated with an elevated frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells. J. Infect. Dis. 199: 1318-1322.
55. Chege, D., Y. Chai, S. Huibner, T. Kain, C. Wachihi, M. Kimani, S. Barasa, L. R. McKinnon, F. K. Muriuki, A. Kariri, et al. 2012. Blunted IL17/IL22 and pro-inflammatory cytokine responses in the genital tract and blood of HIVexposed, seronegative female sex workers in Kenya. PLoS ONE 7: e43670.
56. McLaren, P. J., T. B. Ball, C. Wachihi, W. Jaoko, D. J. Kelvin, A. Danesh, J. Kimani, F. A. Plummer, and K. R. Fowke. 2010. HIV-exposed seronegative commercial sex workers show a quiescent phenotype in the CD4+ T cell compartment and reduced expression of HIV-dependent host factors. J. Infect. Dis. 202(Suppl. 3): S339-S344.