In vitro inhibition of HIV-1 replication in autologous CD4+ T cells indicates viral containment by multifactorial mechanisms

  • Ting Tu
  • Jianbo Zhan
  • Danlei Mou
  • Wei Li
  • Bin Su
  • Tong Zhang
  • Tao Li
  • Ning Li
  • Hao Wu
  • Cong Jin
  • Huabiao Chen
Research Article

Abstract

HIV-1-specific cytotoxic T lymphocytes (CTLs) and neutralizing antibodies (NAbs) are present during chronic infection, but the relative contributions of these effector mechanisms to viral containment remain unclear. Here, using an in vitro model involving autologous CD4+ T cells, primary HIV-1 isolates, HIV-1-specific CTLs, and neutralizing monoclonal antibodies, we show that b12, a potent and broadly neutralizing monoclonal antibody to HIV-1, was able to block viral infection when preincubated with virus prior to infection, but was much less effective than CTLs at limiting virus replication when added to infected cell cultures. However, the same neutralizing antibody was able to contain viruses by antibody-dependent cell-mediated virus inhibition in vitro, which was mediated by natural killer cells (NKs) and dependent on an Fc-Fc receptor interaction. Meanwhile, bulk CTLs from HIV-1 controllers were more effective in suppression of virus replication than those from progressors. These findings indicate that control of HIV-1 replication in activated CD4+ T cells is ineffectively mediated by neutralizing antibodies alone, but that both CTLs and antibody-dependent NK-mediated immune mechanisms contribute to viral containment. Our study systemically compared three major players in controlling HIV-1 infection, CTLs, NAbs, and NKs, in an autologous system and highlighted the multifactorial mechanisms for viral containment and vaccine success.

Keywords

HIV-1 infection viral replication cytotoxic T lymphocyte (CTL) natural killer cells neutralizing antibody 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Addo MM, Yu XG, Rathod A, Cohen D, Eldridge RL, Strick D, Johnston MN, Corcoran C, Wurcel AG, Fitzpatrick CA, et al. 2003. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J Virol, 77: 2081–2092.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Asmal M, Sun Y, Lane S, Yeh W, Schmidt SD, Mascola JR, Letvin NL. 2011. Antibody-dependent cell-mediated viral inhibition emerges after simian immunodeficiency virus SIVmac251 infection of rhesus monkeys coincident with gp140-binding antibodies and is effective against neutralization-resistant viruses. J Virol, 85: 5465–5475.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bailey JR, Lassen KG, Yang HC, Quinn TC, Ray SC, Blankson JN, Siliciano RF. 2006. Neutralizing Antibodies Do Not Mediate Suppression of Human Immunodeficiency Virus Type 1 in Elite Suppressors or Selection of Plasma Virus Variants in Patients on Highly Active Antiretroviral Therapy. J Virol, 80: 4758–4770.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, Lederman MM, Benito JM, Goepfert PA, Connors M, Roederer M, Koup RA. 2006. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood, 107: 4781–4789.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Binley JM, Wrin T, Korber B, Zwick MB, Wang M, Chappey C, Stiegler G, Kunert R, Zolla-Pazner S, Katinger H, Petropoulos CJ, Burton DR. 2004. Comprehensive Cross-Clade Neutralization Analysis of a Panel of Anti-Human Immunodeficiency Virus Type 1 Monoclonal Antibodies. J Virol, 78: 13232–13252.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bonaparte MI, Barker E. 2004. Killing of human immunodefi-ciency virus-infected primary T-cell blasts by autologous natural killer cells is dependent on the ability of the virus to alter the expression of major histocompatibility complex class I molecules. Blood, 104: 2087–2094.CrossRefPubMedGoogle Scholar
  7. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. 1994. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol, 68: 6103–6110.PubMedPubMedCentralGoogle Scholar
  8. Burton DR, Pyati J, Koduri R, Sharp SJ, Thornton GB, Parren PW, Sawyer LS, Hendry RM, Dunlop N, Nara PL, et a. 1994. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science, 266: 1024–1027.CrossRefPubMedGoogle Scholar
  9. Cao Y, Qin L, Zhang L, Safrit J, Ho DD. 1995. Virologic and Immunologic Characterization of Long-Term Survivors of Human Immunodeficiency Virus Type 1 Infection. N Engl J Med, 332: 201–208.CrossRefPubMedGoogle Scholar
  10. Chen H, Ndhlovu ZM, Liu D, Porter LC, Fang JW, Darko S, Brockman MA, Miura T, Brumme ZL, Schneidewind A, et al. 2012. TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection. Nat Immunol, 13: 691–700.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chen H, Piechocka-Trocha A, Miura T, Brockman MA, Julg BD, Baker BM, Rothchild AC, Block BL, Schneidewind A, Koibuchi T, Pereyra F, Allen TM, Walker BD. 2009. Differential Neutralization of Human Immunodeficiency Virus (HIV) Replication in Autologous CD4 T Cells by HIV-Specific Cytotoxic T Lymphocytes. J Virol, 83: 3138–3149.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Deeks SG, Walker BD. 2007. Human Immunodeficiency Virus Controllers: Mechanisms of Durable Virus Control in the Absence of Antiretroviral Therapy. Immunity, 27: 406–416.CrossRefPubMedGoogle Scholar
  13. Emini EA, Schleif WA, Nunberg JH, Conley AJ, Eda Y, Tokiyoshi S, Putney SD, Matsushrta S, Cobb KE, Jett CM, Eichberg JW, Murthy KK. 1992. Prevention of HIV-1 infection in chimpanzees by gpl20 V3 domain-specific monoclonal antibody. Nature, 355: 728–730.CrossRefPubMedGoogle Scholar
  14. Flynn NM FD, Harro CD, Judson FN, Mayer KH, Para MF; The rgp120 HIV Vaccine Study Group. 2005. Placebo-Controlled Phase 3 Trial of a Recombinant Glycoprotein 120 Vaccine to Prevent HIV-1 Infection. J Infect Dis, 191: 654–665.CrossRefPubMedGoogle Scholar
  15. Forthal DN, Landucci G, Cole KS, Marthas M, Becerra JC, Van Rompay K. 2006. Rhesus macaque polyclonal and monoclonal antibodies inhibit simian immunodeficiency virus in the presence of human or autologous rhesus effector cells. J Virol, 80: 9217–9225.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Forthal DN, Landucci G, Daar ES. 2001. Antibody from Patients with Acute Human Immunodeficiency Virus (HIV) Infection Inhibits Primary Strains of HIV Type 1 in the Presence of Natural-Killer Effector Cells. J Virol, 75: 6953–6961.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Forthal DN, Landucci G, Phan TB, Becerra J. 2005. Interactions between Natural Killer Cells and Antibody Fc Result in Enhanced Antibody Neutralization of Human Immunodeficiency Virus Type 1. J Virol, 79: 2042–2049.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Gilbert PB, Berger JO, Stablein D, Becker S, Essex M, Hammer SM, Kim JH, Degruttola VG. 2011. Statistical interpretation of the RV144 HIV vaccine efficacy trial in Thailand: a case study for statistical issues in efficacy trials. J Infect Dis, 203: 969–975.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Harrer T, Harrer E, Kalams SA, Elbeik T, Staprans SI, Feinberg MB, Cao Y, Ho DD, Yilma T, Caliendo AM, Johnson RP, Buchbinder SP, Walker BD. 1996. Strong cytotoxic T cell and weak neutralizing antibody responses in a subset of persons with stable nonprogressing HIV type 1 infection. AIDS Res Hum Retroviruses, 12: 585–592.CrossRefPubMedGoogle Scholar
  20. Hessell AJ, Hangartner L, Hunter M, Havenith CEG, Beurskens FJ, Bakker JM, Lanigan CMS, Landucci G, Forthal DN, Parren PWHI, Marx PA, Burton DR. 2007. Fc receptor but not complement binding is important in antibody protection against HIV. Nature, 449: 101–104.CrossRefPubMedGoogle Scholar
  21. Hezareh M, Hessell AJ, Jensen RC, van de Winkel JGJ, Parren PWHI. 2001. Effector Function Activities of a Panel of Mutants of a Broadly Neutralizing Antibody against Human Immunodeficiency Virus Type 1. J Virol, 75: 12161–12168.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kahn JO, Walker BD. 1998. Acute Human Immunodeficiency Virus Type 1 Infection. N Engl J Med, 339: 33–39.CrossRefPubMedGoogle Scholar
  23. Kim JH, Excler JL, Michael NL. 2015. Lessons from the RV144 Thai phase III HIV-1 vaccine trial and the search for correlates of protection. Annu Rev Med, 66: 423–437.CrossRefPubMedGoogle Scholar
  24. Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, Farthing C, Ho DD. 1994. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol, 68: 4650–4655.PubMedPubMedCentralGoogle Scholar
  25. Liu Q, Sun Y, Rihn S, Nolting A, Tsoukas PN, Jost S, Cohen K, Walker B, Alter G. 2009. Matrix Metalloprotease inhibitors restore impaired NK cell mediated Antibody dependent cellular cytotoxicity in human immunodeficiency virus-1 infection. J Virol, 83: 8705–8712.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Mascola JR, Stiegler G, VanCott TC, Katinger H, Carpenter CB, Hanson CE, Beary H, Hayes D, Frankel SS, Birx DL, Lewis MG. 2000. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med, 6: 207–210.CrossRefPubMedGoogle Scholar
  27. Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, Hallahan CW, Van Baarle D, Kostense S, Miedema F, McLaughlin M, Ehler L, Metcalf J, Liu S, Connors M. 2002. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol, 3: 1061–1068.CrossRefPubMedGoogle Scholar
  28. Moog C, Fleury HJ, Pellegrin I, Kirn A, Aubertin AM. 1997. Autologous and heterologous neutralizing antibody responses following initial seroconversion in human immunodeficiency virus type 1-infected individuals. J Virol, 71: 3734–3741.PubMedPubMedCentralGoogle Scholar
  29. Moore JP, Cao Y, Ho DD, Koup RA. 1994. Development of the anti-gp120 antibody response during seroconversion to human immunodeficiency virus type 1. J Virol, 68: 5142–5155.PubMedPubMedCentralGoogle Scholar
  30. Nie J, Zhao J, Chen Q, Huang W, Wang Y. 2014. Three amino acid residues in the envelope of human immunodeficiency virus type 1 CRF07_BC regulate viral neutralization susceptibility to the human monoclonal neutralizing antibody IgG1b12. Virol Sin, 29: 299–307.CrossRefPubMedGoogle Scholar
  31. Pereyra F, Addo MM, Kaufmann DE, Liu Y, Miura T, Rathod A, Baker B, Trocha A, Rosenberg R, Mackey E, Ueda P, Lu Z, Cohen D, Wrin T, Petropoulos CJ, Rosenberg ES, Walker BD. 2008. Genetic and Immunologic Heterogeneity among Persons Who Control HIV Infection in the Absence of Therapy. J Infect Dis, 197: 563–571.CrossRefPubMedGoogle Scholar
  32. Saez-Cirion A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, Boufassa F, Barre-Sinoussi F, Delfraissy JF, Sinet M, Pancino G, Venet A. 2007. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci U S A, 104: 6776–6781.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Schmitz JE, Johnson RP, McClure HM, Manson KH, Wyand MS, Kuroda MJ, Lifton MA, Khunkhun RS, McEvers KJ, Gillis J, et al. 2005. Effect of CD8+ Lymphocyte Depletion on Virus Containment after Simian Immunodeficiency Virus SIVmac251 Challenge of Live Attenuated SIVmac239{Delta}3-Vaccinated Rhesus Macaques. J Virol, 79: 8131–8141.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA. 1999. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science, 283: 857–860.CrossRefPubMedGoogle Scholar
  35. Someya K, Cecilia D, Ami Y, Nakasone T, Matsuo K, Burda S, Yamamoto H, Yoshino N, Kaizu M, Ando S, Okuda K, Zolla- Pazner S, Yamazaki S, Yamamoto N, Honda M. 2005. Vaccination of Rhesus Macaques with Recombinant Mycobacterium bovis Bacillus Calmette-Guerin Env V3 Elicits Neutralizing Antibody-Mediated Protection against Simian-Human Immunodeficiency Virus with a Homologous but Not a Heterologous V3 Motif. J Virol, 79: 1452–1462.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Trkola A, Pomales AB, Yuan H, Korber B, Maddon PJ, Allaway GP, Katinger H, Barbas CF, 3rd, Burton DR, Ho DD. 1995. Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG. J Virol, 69: 6609–6617.PubMedPubMedCentralGoogle Scholar
  37. Vieillard V, Strominger JL, Debre P. 2005. NK cytotoxicity against CD4+ T cells during HIV-1 infection: a gp41 peptide induces the expression of an NKp44 ligand. Proc Natl Acad Sci U S A, 102: 10981–10986.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Walker BD, Burton DR. 2008. Toward an AIDS Vaccine. Science, 320: 760–764.CrossRefPubMedGoogle Scholar
  39. Wang Z, Qin C, Hu J, Guo X, Yin J. 2016. Recent advances in synthetic carbohydrate-based human immunodeficiency virus vaccines. Virol Sin, 31: 110–117.CrossRefPubMedGoogle Scholar
  40. Wilson CC, Wong JT, Girard DD, Merrill DP, Dynan M, An DD, Kalams SA, Johnson RP, Hirsch MS, D’Aquila RT, et al. 1995. Ex vivo expansion of CD4 lymphocytes from human immunodeficiency virus type 1-infected persons in the presence of combination antiretroviral agents. J Infect Dis, 172: 88–96.CrossRefPubMedGoogle Scholar
  41. Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, Richman DD. 1997. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science, 278: 1291–1295.CrossRefPubMedGoogle Scholar
  42. Yang OO, Kalams SA, Rosenzweig M, Trocha A, Jones N, Koziel M, Walker BD, Johnson RP. 1996. Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes. J Virol, 70: 5799–5806.PubMedPubMedCentralGoogle Scholar
  43. Yang OO, Kalams SA, Trocha A, Cao H, Luster A, Johnson RP, Walker BD. 1997. Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms. J Virol, 71: 3120–3128.PubMedPubMedCentralGoogle Scholar
  44. Yang OO, Nguyen PT, Kalams SA, Dorfman T, Gottlinger HG, Stewart S, Chen IS, Threlkeld S, Walker BD. 2002. Nef-mediated resistance of human immunodeficiency virus type 1 to antiviral cytotoxic T lymphocytes. J Virol, 76: 1626–1631.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Yang OO, Sarkis PT, Trocha A, Kalams SA, Johnson RP, Walker BD. 2003. Impacts of avidity and specificity on the antiviral efficiency of HIV-1-specific CTL. J Immunol, 171: 3718–3724.CrossRefPubMedGoogle Scholar
  46. Zimmerli SC, Harari A, Cellerai C, Vallelian F, Bart PA, Pantaleo G. 2005. HIV-1-specific IFN-gamma/IL-2-secreting CD8 T cells support CD4-independent proliferation of HIV-1-specific CD8 T cells. Proc Natl Acad Sci U S A, 102: 7239–7244.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Jiangsu Key Laboratory of Clinical Laboratory MedicineJiangsu University School of MedicineZhenjiangChina
  2. 2.National HIV/HCV Reference Laboratory, National Center for AIDS/STD Control and PreventionChinese Center for Disease Control and PreventionBeijingChina
  3. 3.Hubei Provincial Center for Disease Control and PreventionWuhanChina
  4. 4.Beijing You’an HospitalCapital Medical UniversityBeijingChina

Personalised recommendations