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Preferential loss of gut-homing α4β7 CD4+ T cells and their circulating functional subsets in acute HIV-1 infection

Cellular & Molecular Immunology volume 13, pages 776–784 (2016)Cite this article

Abstract

Preferential infection and depletion of gut-homing α4β7 CD4+ T cells in the blood are observed in chronic HIV/SIV infection. The dynamic change in gut-homing α4β7 CD4+ T cells and their functional subsets during the acute stages of HIV-1 infection are less documented. Therefore, we conducted a cohort study to investigate whether acute HIV-1 infection induced abnormalities in gut-homing α4β7 CD4+ T cells and their functional subsets. We examined the frequency, absolute number, and functionality of gut-homing α4β7 CD4+ T cells in 26 acute HIV-1-infected patients compared with 20 healthy individuals. We found that circulating gut-homing α4β7 CD4+ T cells were preferentially depleted during acute HIV-1 infection and were positively correlated with absolute CD4+ T-cell count in blood. Notably, Th17 and Th1 cell subsets of gut-homing CD4+ T cells were also decreased, which resulted in an imbalance of T helper cells (Th1):regulatory T cells (Treg) and Treg:Th17 ratios. Gut-homing Th17 and Th1 cells were also positively correlated with the absolute number of total CD4+ T cells and gut-homing CD4+ T cells. The gut-homing Treg:Th17 ratio was inversely correlated with the CD4+ T-cell count. Taken together, the analyses of our acute HIV-1 cohort demonstrate that gut-homing α4β7 CD4+ T cells and their functional subsets were profoundly depleted during acute HIV-1 infection, which may have resulted in the persistent loss of circulating CD4+ T cells and an imbalance of Th1:Treg and Treg:Th17 ratios and contribute to HIV-1 disease pathogenesis.

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References

  1. Holmgren J, Czerkinsky C . Mucosal immunity and vaccines. Nat Med 2005; 11: S45–S53.

    Article  CAS  PubMed  Google Scholar 

  2. Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, Hogan C et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 2004; 200:761–770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Veazey RS, Marx PA, Lackner AA . Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection. J Infect Dis 2003; 187: 769–776.

    Article  CAS  PubMed  Google Scholar 

  4. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 2004; 200: 749–759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M . Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 2005; 434: 1093–1097.

    Article  CAS  PubMed  Google Scholar 

  6. Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G, Hallahan CW et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis 2008; 197: 714–720.

    Article  CAS  PubMed  Google Scholar 

  7. Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J, McNeil A et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 2003; 77: 11708–11717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mehandru S, Poles MA, Tenner-Racz K, Jean-Pierre P, Manuelli V, Lopez P et al. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med 2006; 3: e484 .

    Article  PubMed  PubMed Central  Google Scholar 

  9. Rueda CM, Velilla PA, Chougnet CA, Montoya CJ, Rugeles MT . HIV-induced T-cell activation/exhaustion in rectal mucosa is controlled only partially by antiretroviral treatment. PLoS One 2012; 7: e30307 .

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bixler SL, Mattapallil JJ . Loss and dysregulation of Th17 cells during HIV infection. Clin Dev Immunol 2013; 2013: 852418 .

    Article  PubMed  PubMed Central  Google Scholar 

  11. Chege D, Sheth PM, Kain T, Kim CJ, Kovacs C, Loutfy M et al. Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy. AIDS 2011; 25: 741–749.

    Article  CAS  PubMed  Google Scholar 

  12. Macal M, Sankaran S, Chun TW, Reay E, Flamm J, Prindiville TJ et al. Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses. Mucosal Immunol 2008; 1: 475–488.

    Article  CAS  PubMed  Google Scholar 

  13. Nigam P, Kwa S, Velu V, Amara RR . Loss of IL-17-producing CD8 T cells during late chronic stage of pathogenic simian immunodeficiency virus infection. J Immunol 2011; 186: 745–753.

    Article  CAS  PubMed  Google Scholar 

  14. Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, Winter SE et al. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med 2008; 14: 421–428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brandt L, Benfield T, Mens H, Clausen LN, Katzenstein TL, Fomsgaard A et al. Low level of regulatory T cells and maintenance of balance between regulatory T cells and TH17 cells in HIV-1-infected elite controllers. J Acquir Immune Defic Syndr 2011; 57: 101–108.

    Article  CAS  PubMed  Google Scholar 

  16. Cecchinato V, Trindade CJ, Laurence A, Heraud JM, Brenchley JM, Ferrari MG et al. Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal Immunol 2008; 1: 279–288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. He Y, Li J, Zheng Y, Luo Y, Zhou H, Yao Y et al. A randomized case-control study of dynamic changes in peripheral blood Th17/Treg cell balance and interleukin-17 levels in highly active antiretroviral-treated HIV type 1/AIDS patients. AIDS Res Hum Retroviruses 2012; 28: 339–345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 1993; 74: 185–195.

    Article  CAS  PubMed  Google Scholar 

  19. Wagner N, Lohler J, Kunkel EJ, Ley K, Leung E, Krissansen G et al. Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue. Nature 1996; 382: 366–370.

    Article  CAS  PubMed  Google Scholar 

  20. Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D et al. HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 2008; 9: 301–309.

    Article  CAS  PubMed  Google Scholar 

  21. Cicala C, Martinelli E, McNally JP, Goode DJ, Gopaul R, Hiatt J et al. The integrin alpha4beta7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1. Proc Natl Acad Sci USA 2009; 106: 20877–20882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kader M, Wang X, Piatak M, Lifson J, Roederer M, Veazey R et al. Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection. Mucosal Immunol 2009; 2: 439–449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Krzysiek R, Rudent A, Bouchet-Delbos L, Foussat A, Boutillon C, Portier A et al. Preferential and persistent depletion of CCR5+ T-helper lymphocytes with nonlymphoid homing potential despite early treatment of primary HIV infection. Blood 2001; 98: 3169–3171.

    Article  CAS  PubMed  Google Scholar 

  24. Mavigner M, Cazabat M, Dubois M, L’Faqihi FE, Requena M, Pasquier C et al. Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J Clin Invest 2012; 122: 62–69.

    Article  CAS  PubMed  Google Scholar 

  25. Peng Q, Wang H, Wang H, Li X, Lu X, Liu L et al. Imbalances of gut-homing CD4+ T-cell subsets in HIV-1-infected Chinese patients. J Acquir Immune Defic Syndr 2013; 64: 25–31.

    Article  PubMed  Google Scholar 

  26. Ciccone EJ, Read SW, Mannon PJ, Yao MD, Hodge JN, Dewar R et al. Cycling of gut mucosal CD4+ T cells decreases after prolonged anti-retroviral therapy and is associated with plasma LPS levels. Mucosal Immunol 2010; 3: 172–181.

    Article  CAS  PubMed  Google Scholar 

  27. Wang X, Xu H, Gill AF, Pahar B, Kempf D, Rasmussen T et al. Monitoring alpha4beta7 integrin expression on circulating CD4+ T cells as a surrogate marker for tracking intestinal CD4+ T-cell loss in SIV infection. Mucosal Immunol 2009; 2: 518–526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12: 1365–1371.

    Article  CAS  PubMed  Google Scholar 

  29. Douek DC, Roederer M, Koup RA . Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med 2009; 60: 471–484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Okoye AA, Picker LJ . CD4(+) T-cell depletion in HIV infection: mechanisms of immunological failure. Immunol Rev 2013; 254: 54–64.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chase AJ, Sedaghat AR, German JR, Gama L, Zink MC, Clements JE et al. Severe depletion of CD4+ CD25+ regulatory T cells from the intestinal lamina propria but not peripheral blood or lymph nodes during acute simian immunodeficiency virus infection. J Virol 2007; 81: 12748–12757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang X, Xu H, Shen C, Alvarez X, Liu D, Pahar B et al. Profound loss of intestinal Tregs in acutely SIV-infected neonatal macaques. J Leukoc Biol 2015; 97: 391–400.

    Article  PubMed  Google Scholar 

  33. Chevalier MF, Petitjean G, Dunyach-Remy C, Didier C, Girard PM, Manea ME et al. The Th17/Treg ratio, IL-1RA and sCD14 levels in primary HIV infection predict the T-cell activation set point in the absence of systemic microbial translocation. PLoS Pathog 2013; 9: e1003453 .

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Favre D, Lederer S, Kanwar B, Ma ZM, Proll S, Kasakow Z et al. Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog 2009; 5: e1000295 .

    Article  PubMed  PubMed Central  Google Scholar 

  35. Schuetz A, Deleage C, Sereti I, Rerknimitr R, Phanuphak N, Phuang-Ngern Y et al. Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLoS Pathog 2014; 10: e1004543 .

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ciccone EJ, Greenwald JH, Lee PI, Biancotto A, Read SW, Yao MA et al. CD4+ T cells, including Th17 and cycling subsets, are intact in the gut mucosa of HIV-1-infected long-term nonprogressors. J Virol 2011; 85: 5880–5888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This project was supported by the 12th Five-Year Mega Project of China on the prevention and treatment of AIDS, viral hepatitis and other infectious disease (2014ZX10001002-001-002, 2012ZX10001-006), the Beijing Municipal of Science and Technology Major Project (D141100000314005), and Beijing Natural Science Foundation (7132077). We also thank the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZY201401) and the Beijing Key Laboratory for HIV/AIDS Research (BZ0089) for financial support for this work.

Author information

Author notes

  1. Xiaofan Lu, Zhen Li and Qunhui Li: X Lu, Z Li, and Q Li contributed equally to this work.

  2. Dr. W Li, Center for Infectious Diseases, Beijing You-An Hospital, Capital Medical University, Beijing 100069, People’s Republic of China. E-mail: vision988@126.com

  3. Dr. H Wu, Center for Infectious Diseases, Beijing You-An Hospital, Capital Medical University, Beijing 100069 People’s Republic of China. E-mail: whdoc@sina.com

Authors and Affiliations

  1. STD/HIV Research Laboratory, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China

    Xiaofan Lu, Zhen Li, Yanmei Jiao, Yunxia Ji & Wei Li

  2. Beijing Key Laboratory for HIV/AIDS Research, Beijing, 100069, People’s Republic of China

    Xiaofan Lu, Zhen Li, Yanmei Jiao, Yunxia Ji & Wei Li

  3. Center for Infectious Diseases, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China

    Qunhui Li, Hongwei Zhang, Wei Li & Hao Wu

  4. Case Comprehensive Cancer Center and Department of Pathology, Case Western Reserve University, Cleveland, 44106, OH, USA

    Zhuoming Liu

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Lu, X., Li, Z., Li, Q. et al. Preferential loss of gut-homing α4β7 CD4+ T cells and their circulating functional subsets in acute HIV-1 infection. Cell Mol Immunol 13, 776–784 (2016). https://doi.org/10.1038/cmi.2015.60

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