Skip to main content

Advertisement

Log in

Clinical implications of discordant viral and immune outcomes following protease inhibitor containing antiretroviral therapy for HIV-infected children

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Many HIV-infected children treated with protease inhibitors (PI) reconstitute immunity despite viral breakthrough predicting disease progression. We studied a unique cohort of PI treated children with advanced disease who demonstrated sustained CD4 T cell counts but median post therapy viral load rebounded to >4.0 log10 copies/ml. Phylogenetic relationships between pre- and post-therapy viruses reveals significant bottlenecks for quasispecies with natural polymorphisms mapping outside of protease active site providing selective advantage for emergence. Among discordant subjects post-therapy viruses fell into two phenotypes; high viral loads (median >5.0 log10 copies/ml) and attenuated post-therapy replication (median <4.0 log10 copies/ml). Both groups showed similar degrees of CD4 T cell immune reconstitution and were similar to children who optimally suppressed virus to <400 copies/ml. Both high fit and low fit discordant response groups showed high reconstitution of naïve CD4 CD45RA T cells (median 388 and 357 cells/μl, respectively). Naïve T cells increases suggest virus replicating under PI selective pressure do not impair thymic output. If therapeutic options are limited, selection of therapy which allows immune reconstitution despite suboptimal viral control may be beneficial. This novel paradigm for virus/host interactions may lead to therapeutic approaches to attenuate viral pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Detels R, Munoz A, McFarlane G, Kingsley LA, Margolick JB, Giorgi J, Schrager LK, Phair JP. Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Muliticenter AIDS Cohort Study Investigators. Jama 1998;280:1497–503.

    Article  PubMed  CAS  Google Scholar 

  2. Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med 2002;137:381–433.

    PubMed  Google Scholar 

  3. Palella FJ Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338:853–60.

    Article  PubMed  Google Scholar 

  4. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Center for Disease Control and Prevention. MMWR Recomm Rep 1998;47:1–43.

    Google Scholar 

  5. Guidelines for the Use of Antiretroviral Agents in HIV–1-Infected Adults and Adolescents. A Working Group of the Office of AIDS Research Advisory Council (OARAC). 2006.

  6. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children. 2006.

  7. Flynn PM, Rudy BJ, Douglas SD, Lathey J, Spector SA, Martinez J, Silio M, Belzer M, Friedman L, D’Angelo L, McNamara J, Hodge J, Hughes MD, Lindsey JC. Virologic and immunologic outcomes after 24 weeks in HIV type 1-infected adolescents receiving highly active antiretroviral therapy. J Infect Dis 2004;190:271–9.

    Article  PubMed  CAS  Google Scholar 

  8. Ledergerber B, Egger M, Opravil M, Telenti A, Hirschel B, Battegay M, Vernazza P, Sudre P, Flepp M, Furrer H, Francioli P, Weber R. Clinical progression and virological failure on highly active antiretroviral therapy in HIV–1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet 1999;353:863–8.

    Article  PubMed  CAS  Google Scholar 

  9. Nachman SA, Stanley K, Yogev R, Pelton S, Wiznia A, Lee S, Mofenson L, Fiscus S, Rathore M, Jimenez E, Borkowsky W, Pitt J, Smith ME, Wells B, McIntosh K. Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 Study Team. Jama 2000;283:492–8.

    Article  PubMed  CAS  Google Scholar 

  10. Deeks SG, Barbour JD, Martin JN, Swanson MS, Grant RM. Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. J Infect Dis 2000;181:946–53.

    Article  PubMed  CAS  Google Scholar 

  11. Essajee SM, Kim M, Gonzalez C, Rigaud M, Kaul A, Chandwani S, Hoover W, Lawrence R, Spiegel H, Pollack H, Krasinski K, Borkowsky W. Immunologic and virologic responses to HAART in severely immunocompromised HIV-1-infected children. Aids 1999;13:2523–32.

    Article  PubMed  CAS  Google Scholar 

  12. Ghaffari G, Passalacqua DJ, Caicedo JL, Goodenow MM, Sleasman JW. Two-year clinical and immune outcomes in human immunodeficiency virus-infected children who reconstitute CD4 T cells without control of viral replication after combination antiretroviral therapy. Pediatrics 2004;114:e604–11.

    Article  PubMed  Google Scholar 

  13. Perez EE, Rose SL, Peyser B, Lamers SL, Burkhardt B, Dunn BM, Hutson AD, Sleasman JW, Goodenow MM. Human immunodeficiency virus type 1 protease genotype predicts immune and viral responses to combination therapy with protease inhibitors (PIs) in PI-naive patients. J Infect Dis 2001;183:579–88.

    Article  PubMed  CAS  Google Scholar 

  14. Sleasman JW, Nelson RP, Goodenow MM, Wilfret D, Hutson A, Baseler M, Zuckerman J, Pizzo PA, Mueller BU. Immunoreconstitution after ritonavir therapy in children with human immunodeficiency virus infection involves multiple lymphocyte lineages. J Pediatr 1999;134:597–606.

    Article  PubMed  CAS  Google Scholar 

  15. Jankelevich S, Mueller BU, Mackall CL, Smith S, Zwerski S, Wood LV, Zeichner SL, Serchuck L, Steinberg SM, Nelson RP, Sleasman JW, Nguyen BY, Pizzo PA, Yarchoan R. Long-term virologic and immunologic responses in human immunodeficiency virus type 1-infected children treated with indinavir, zidovudine, and lamivudine. J Infect Dis 2001;183:1116–20.

    Article  PubMed  CAS  Google Scholar 

  16. Peruzzi M, Azzari C, Galli L, Vierucci A, De Martino M. Highly active antiretroviral therapy restores in vitro mitogen and antigen-specific T-lymphocyte responses in HIV-1 perinatally infected children despite virological failure. Clin Exp Immunol 2002;128:365–71.

    Article  PubMed  CAS  Google Scholar 

  17. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age [and] official authorized addenda: human immunodeficiency virus infection codes and official guidelines for coding and reporting ICD–9-CM. Corp Authors: Centers for Disease Control and Prevention (U.S). Atlanta, GA, U.S. Dept. of Health and Human Services Public Health Service Centers for Disease Control and Prevention (CDC). 1994.

  18. Deeks SG, Barbour JD, Grant RM, Martin JN. Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. Aids 2002;16:201–7.

    Article  PubMed  Google Scholar 

  19. Le Moing V, Thiebaut R, Chene G, Leport C, Cailleton V, Michelet C, Fleury H, Herson S, Raffi F. Predictors of long-term increase in CD4(+) cell counts in human immunodeficiency virus-infected patients receiving a protease inhibitor-containing antiretroviral regimen. J Infect Dis 2002;185:471–80.

    Article  PubMed  CAS  Google Scholar 

  20. Sufka SA, Ferrari G, Gryszowka VE, Wrin T, Fiscus SA, Tomaras GD, Staats HF, Patel DD, Sempowski GD, Hellmann NS, Weinhold KJ, Hicks CB. Prolonged CD4+ cell/virus load discordance during treatment with protease inhibitor-based highly active antiretroviral therapy: immune response and viral control. J Infect Dis 2003;187:1027–37.

    Article  PubMed  CAS  Google Scholar 

  21. Desrosiers RC, Lifson JD, Gibbs JS, Czajak SC, Howe AY, Arthur LO, Johnson RP. Identification of highly attenuated mutants of simian immunodeficiency virus. J Virol 1998;72:1431–7.

    PubMed  CAS  Google Scholar 

  22. Greenough TC, Sullivan JL, Desrosiers RC. Declining CD4 T-cell counts in a person infected with nef-deleted HIV-1. N Engl J Med 1999;340:236–7.

    Article  PubMed  CAS  Google Scholar 

  23. Hendel H, Henon N, Lebuanec H, Lachgar A, Poncelet H, Caillat-Zucman S, Winkler CA, Smith MW, Kenefic L, O’Brien S, Lu W, Andrieu JM, Zagury D, Schachter F, Rappaport J, Zagury JF. Distinctive effects of CCR5, CCR2, and SDF1 genetic polymorphisms in AIDS progression. J Acquir Immune Defic Syndr Hum Retrovirol 1998;19:381–6.

    PubMed  CAS  Google Scholar 

  24. Lee B, Doranz BJ, Rana S, Yi Y, Mellado M, Frade JM, Martinez AC, O’Brien SJ, Dean M, Collman RG, Doms RW. Influence of the CCR2-V64I polymorphism on human immunodeficiency virus type 1 coreceptor activity and on chemokine receptor function of CCR2b, CCR3, CCR5, and CXCR4. J Virol 1998;72:7450–8.

    PubMed  CAS  Google Scholar 

  25. Mariani R, Kirchhoff F, Greenough TC, Sullivan JL, Desrosiers RC, Skowronski J. High frequency of defective nef alleles in a long-term survivor with nonprogressive human immunodeficiency virus type 1 infection. J Virol 1996;70:7752–64.

    PubMed  CAS  Google Scholar 

  26. Mariani R, Wong S, Mulder LC, Wilkinson DA, Reinhart AL, LaRosa G, Nibbs R, O’Brien TR, Michael NL, Connor RI, Macdonald M, Busch M, Koup RA, Landau NR. CCR2–64I polymorphism is not associated with altered CCR5 expression or coreceptor function. J Virol 1999;73:2450–9.

    PubMed  CAS  Google Scholar 

  27. Martin MP, Dean M, Smith MW, Winkler C, Gerrard B, Michael NL, Lee B, Doms RW, Margolick J, Buchbinder S, Goedert JJ, O’Brien TR, Hilgartner MW, Vlahov D, O’Brien SJ, Carrington M. Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science 1998;282:1907–11.

    Article  PubMed  CAS  Google Scholar 

  28. Michael NL, Nelson JA, KewalRamani VN, Chang G, O’Brien SJ, Mascola JR, Volsky B, Louder M, White GC 2nd, Littman DR, Swanstrom R, O’Brien TR. Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32. J Virol 1998;72:6040–7.

    PubMed  CAS  Google Scholar 

  29. Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, Dean M, Honjo T, Tashiro K, Yabe D, Buchbinder S, Vittinghoff E, Goedert JJ, O’Brien TR, Jacobson LP, Detels R, Donfield S, Willoughby A, Gomperts E, Vlahov D, Phair J, O’Brien SJ. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science 1998;279:389–93.

    Article  PubMed  CAS  Google Scholar 

  30. Wyand MS, Manson K, Montefiori DC, Lifson JD, Johnson RP, Desrosiers RC. Protection by live, attenuated simian immunodeficiency virus against heterologous challenge. J Virol 1999;73:8356–63.

    PubMed  CAS  Google Scholar 

  31. Fultz PN, McClure HM, Anderson DC, Swenson RB, Anand R, Srinivasan A: Isolation of a T-lymphotropic retrovirus from naturally infected sooty mangabey monkeys (Cercocebus atys). Proc Natl Acad Sci USA 1986;83:5286–90.

    Article  PubMed  CAS  Google Scholar 

  32. Kaur A, Grant RM, Means RE, McClure H, Feinberg M, Johnson RP. Diverse host responses and outcomes following simian immunodeficiency virus SIVmac239 infection in sooty mangabeys and rhesus macaques. J Virol 1998;72:9597–611.

    PubMed  CAS  Google Scholar 

  33. Harouse JM, Gettie A, Tan RC, Blanchard J, Cheng-Mayer C. Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs. Science 1999;284:816–9.

    Article  PubMed  CAS  Google Scholar 

  34. Goodenow MM, Bloom G, Rose SL, Pomeroy SM, O’Brien PO, Perez EE, Sleasman JW, Dunn BM. Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease. Virology 2002;292:137–49.

    Article  PubMed  CAS  Google Scholar 

  35. Clemente JC, Hemrajani R, Blum LE, Goodenow MM, Dunn BM. Secondary mutations M36I and A71V in the human immunodeficiency virus type 1 protease can provide an advantage for the emergence of the primary mutation D30N. Biochemistry 2003;42:15029–35.

    Article  PubMed  CAS  Google Scholar 

  36. Doyon L, Croteau G, Thibeault D, Poulin F, Pilote L, Lamarre D. Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors. J Virol 1996;70:3763–9.

    PubMed  CAS  Google Scholar 

  37. Ho DD, Toyoshima T, Mo H, Kempf DJ, Norbeck D, Chen CM, Wideburg NE, Burt SK, Erickson JW, Singh MK. Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. J Virol 1994;68:2016–20.

    PubMed  CAS  Google Scholar 

  38. Mammano F, Petit C, Clavel F. Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients. J Virol 1998;72:7632–7.

    PubMed  CAS  Google Scholar 

  39. Zennou V, Mammano F, Paulous S, Mathez D, Clavel F. Loss of viral fitness associated with multiple Gag and Gag-Pol processing defects in human immunodeficiency virus type 1 variants selected for resistance to protease inhibitors in vivo. J Virol 1998;72:3300–6.

    PubMed  CAS  Google Scholar 

  40. Zhang YM, Imamichi H, Imamichi T, Lane HC, Falloon J, Vasudevachari MB, Salzman NP. Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J Virol 1997;71:6662–70.

    PubMed  CAS  Google Scholar 

  41. Barrie KA, Perez EE, Lamers SL, Farmerie WG, Dunn BM, Sleasman JW, Goodenow MM. Natural variation in HIV-1 protease, Gag p7 and p6, and protease cleavage sites within gag/pol polyproteins: amino acid substitutions in the absence of protease inhibitors in mothers and children infected by human immunodeficiency virus type 1. Virology 1996;219:407–16.

    Article  PubMed  CAS  Google Scholar 

  42. Stoddart CA, Liegler TJ, Mammano F, Linquist-Stepps VD, Hayden MS, Deeks SG, Grant RM, Clavel F, McCune JM. Impaired replication of protease inhibitor-resistant HIV–1 in human thymus. Nat Med 2001;7:712–8.

    Article  PubMed  CAS  Google Scholar 

  43. Rose S. Impact by protease inhibitor on evolution on HIV-1 gag-pol in pediatric patients following 24 weeks of therapy [in preparation].

  44. Si-Mohamed A, Kazatchkine MD, Heard I, Goujon C, Prazuck T, Aymard G, Cessot G, Kuo YH, Bernard MC, Diquet B, Malkin JE, Gutmann L, Belec L: Selection of drug-resistant variants in the female genital tract of human immunodeficiency virus type 1-infected women receiving antiretroviral therapy. J Infect Dis 2000;182:112–22.

    Article  PubMed  CAS  Google Scholar 

  45. Picchio GR, Valdez H, Sabbe R, Landay AL, Kuritzkes DR, Lederman MM, Mosier DE. Altered viral fitness of HIV–1 following failure of protease inhibitor-based therapy. J Acquir Immune Defic Syndr 2000;25:289–95.

    Article  PubMed  CAS  Google Scholar 

  46. Deeks SG, Grant RM, Wrin T, Paxinos EE, Liegler T, Hoh R, Martin JN, Petropoulos CJ. Persistence of drug-resistant HIV-1 after a structured treatment interruption and its impact on treatment response. Aids 2003;17:361–70.

    Article  PubMed  CAS  Google Scholar 

  47. Lecossier D, Bouchonnet F, Schneider P, Clavel F, Hance AJ. Discordant increases in CD4+ T cells in human immunodeficiency virus-infected patients experiencing virologic treatment failure: role of changes in thymic output and T cell death. J Infect Dis 2001;183:1009–16.

    Article  PubMed  CAS  Google Scholar 

  48. Lawrence J, Mayers DL, Hullsiek KH, Collins G, Abrams DI, Reisler RB, Crane LR, Schmetter BS, Dionne TJ, Saldanha JM, Jones MC, Baxter JD. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med 2003;349:837–46.

    Article  PubMed  Google Scholar 

  49. Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 1995;374:569–71.

    Article  PubMed  CAS  Google Scholar 

  50. Hatano H, Hunt P, Weidler J, Coakley E, Hoh R, Liegler T, Martin JN, Deeks SG. Rate of viral evolution and risk of losing future drug options in heavily pretreated, HIV-infected patients who continue to receive a stable, partially suppressive treatment regimen. Clin Infect Dis 2006;43:1329–36.

    Article  PubMed  CAS  Google Scholar 

  51. Molla A, Korneyeva M, Gao Q, Vasavanonda S, Schipper PJ, Mo HM, Markowitz M, Chernyavskiy T, Niu P, Lyons N, Hsu A, Granneman GR, Ho DD, Boucher CA, Leonard JM, Norbeck DW, Kempf DJ. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med 1996;2:760–6.

    Article  PubMed  CAS  Google Scholar 

  52. Croteau G, Doyon L, Thibeault D, McKercher G, Pilote L, Lamarre D. Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors. J Virol 1997;71:1089–96.

    PubMed  CAS  Google Scholar 

  53. Goodenow MM, Rose SL, Tuttle DL, Sleasman JW. HIV-1 fitness and macrophages. J Leukoc Biol 2003;74:657–66.

    Article  PubMed  CAS  Google Scholar 

  54. Martinez-Picado J, Savara AV, Sutton L, D’Aquila RT. Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1. J Virol 1999;73:3744–52.

    PubMed  CAS  Google Scholar 

  55. Kaufmann D, Pantaleo G, Sudre P, Telenti A. CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy (HAART). Swiss HIV Cohort Study. Lancet 1998;351:723–4.

    Article  PubMed  CAS  Google Scholar 

  56. Renaud M, Katlama C, Mallet A, Calvez V, Carcelain G, Tubiana R, Jouan M, Caumes E, Agut H, Bricaire F, Debre P, Autran B. Determinants of paradoxical CD4 cell reconstitution after protease inhibitor-containing antiretroviral regimen. Aids 1999;13:669–76.

    Article  PubMed  CAS  Google Scholar 

  57. Mellors JW, Rinaldo CR Jr., Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996;272:1167–70.

    Article  PubMed  CAS  Google Scholar 

  58. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995;373:123–6.

    Article  PubMed  CAS  Google Scholar 

  59. Kourtis AP, Ibegbu C, Nahmias AJ, Lee FK, Clark WS, Sawyer MK, Nesheim S. Early progression of disease in HIV-infected infants with thymus dysfunction. N Engl J Med 1996;335:1431–6.

    Article  PubMed  CAS  Google Scholar 

  60. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998;396:690–5.

    Article  PubMed  CAS  Google Scholar 

  61. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997;277:112–6.

    Article  PubMed  CAS  Google Scholar 

  62. Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, Kuruppu J, Yazdani J, Migueles SA, Connors M, Roederer M, Douek DC, Koup RA. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol 2004;78:1160–8.

    Article  PubMed  CAS  Google Scholar 

  63. Sleasman JW, Aleixo LF, Morton A, Skoda-Smith S, Goodenow MM. CD4+ memory T cells are the predominant population of HIV-1-infected lymphocytes in neonates and children. Aids 1996;10:1477–84.

    Article  PubMed  CAS  Google Scholar 

  64. Sodora DL, Milush JM, Ware F, Wozniakowski A, Montgomery L, McClure HM, Lackner AA, Marthas M, Hirsch V, Johnson RP, Douek DC, Koup RA. Decreased levels of recent thymic emigrants in peripheral blood of simian immunodeficiency virus-infected macaques correlate with alterations within the thymus. J Virol 2002;76:9981–90.

    Article  PubMed  CAS  Google Scholar 

  65. Douek DC, Koup RA, McFarland RD, Sullivan JL, Luzuriaga K. Effect of HIV on thymic function before and after antiretroviral therapy in children. J Infect Dis 2000;181:1479–82.

    Article  PubMed  CAS  Google Scholar 

  66. Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, Berenson JR, Collins RH, Koup RA. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 2000;355:1875–81.

    Article  PubMed  CAS  Google Scholar 

  67. Zhang L, Lewin SR, Markowitz M, Lin HH, Skulsky E, Karanicolas R, He Y, Jin X, Tuttleton S, Vesanen M, Spiegel H, Kost R, van Lunzen J, Stellbrink HJ, Wolinsky S, Borkowsky W, Palumbo P, Kostrikis LG, Ho DD. Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. J Exp Med 1999;190:725–32.

    Article  PubMed  CAS  Google Scholar 

  68. Kou ZC, Puhr JS, Wu SS, Goodenow MM, Sleasman JW. Combination antiretroviral therapy results in a rapid increase in T cell receptor variable region beta repertoire diversity within CD45RA CD8 T cells in human immunodeficiency virus-infected children. J Infect Dis 2003;187:385–97.

    Article  PubMed  CAS  Google Scholar 

  69. Ometto L, De Forni D, Patiri F, Trouplin V, Mammano F, Giacomet V, Giaquinto C, Douek D, Koup R, De Rossi A. Immune reconstitution in HIV-1-infected children on antiretroviral therapy: role of thymic output and viral fitness. Aids 2002;16:839–49.

    Article  PubMed  Google Scholar 

  70. Hellerstein M, Hanley MB, Cesar D, Siler S, Papageorgopoulos C, Wieder E, Schmidt D, Hoh R, Neese R, Macallan D, Deeks S, McCune JM. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med 1999;5:83–9.

    Article  PubMed  CAS  Google Scholar 

  71. McCune JM, Hanley MB, Cesar D, Halvorsen R, Hoh R, Schmidt D, Wieder E, Deeks S, Siler S, Neese R, Hellerstein M. Factors influencing T-cell turnover in HIV-1-seropositive patients. J Clin Invest 2000;105:R1–8.

    Article  PubMed  CAS  Google Scholar 

  72. Sprent J, Tough DF. T cell death and memory. Science 2001;293:245–8.

    Article  PubMed  CAS  Google Scholar 

  73. Hellerstein MK, Hoh RA, Hanley MB, Cesar D, Lee D, Neese RA, McCune JM. Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. J Clin Invest 2003;112:956–66.

    Article  PubMed  CAS  Google Scholar 

  74. Faint JM, Annels NE, Curnow SJ, Shields P, Pilling D, Hislop AD, Wu L, Akbar AN, Buckley CD, Moss PA, Adams DH, Rickinson AB, Salmon M. Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics. J Immunol 2001;167:212–20.

    PubMed  CAS  Google Scholar 

  75. Sleasman JW, Goodenow MM. 13. HIV-1 infection. J Allergy Clin Immunol 2003;111:S582–92.

    Article  PubMed  CAS  Google Scholar 

  76. McMichael AJ, Rowland-Jones SL. Cellular immune responses to HIV. Nature 2001;410:980–7.

    Article  PubMed  CAS  Google Scholar 

  77. Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, Appay V, Rizzardi GP, Fleury S, Lipp M, Forster R, Rowland-Jones S, Sekaly RP, McMichael AJ, Pantaleo G. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 2001;410:106–11.

    Article  PubMed  CAS  Google Scholar 

  78. Appay V, Rowland-Jones SL. Lessons from the study of T-cell differentiation in persistent human virus infection. Semin Immunol 2004;16:205–12.

    Article  PubMed  CAS  Google Scholar 

  79. Lieberman J, Shankar P, Manjunath N, Andersson J. Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection. Blood 2001;98:1667–77.

    Article  PubMed  CAS  Google Scholar 

  80. Kou ZC, Puhr JS, Rojas M, McCormack WT, Goodenow MM, Sleasman JW. T-Cell receptor Vbeta repertoire CDR3 length diversity differs within CD45RA and CD45RO T-cell subsets in healthy and human immunodeficiency virus-infected children. Clin Diagn Lab Immunol 2000;7:953–9.

    Article  PubMed  CAS  Google Scholar 

  81. Connick E, Lederman MM, Kotzin BL, Spritzler J, Kuritzkes DR, St Clair M, Sevin AD, Fox L, Chiozzi MH, Leonard JM, Rousseau F, D’Arc Roe J, Martinez A, Kessler H, Landay A. Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response. J Infect Dis 2000;181:358–63.

    Article  PubMed  CAS  Google Scholar 

  82. Valdez H. Immune restoration after treatment of HIV-1 infection with highly active antiretroviral therapy (HAART). AIDS Rev 2002;4:157–64.

    PubMed  Google Scholar 

  83. Valdez H, Smith KY, Landay A, Connick E, Kuritzkes DR, Kessler H, Fox L, Spritzler J, Roe J, Lederman MB, Lederman HM, Evans TG, Heath-Chiozzi M, Lederman MM. Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen. ACTG 375 team. AIDS Clinical Trials Group. Aids 2000;14:11–21.

    Article  PubMed  CAS  Google Scholar 

  84. Rey-Cuille MA, Berthier JL, Bomsel-Demontoy MC, Chaduc Y, Montagnier L, Hovanessian AG, Chakrabarti LA. Simian immunodeficiency virus replicates to high levels in sooty mangabeys without inducing disease. J Virol 1998;72:3872–86.

    PubMed  CAS  Google Scholar 

  85. Silvestri G, Sodora DL, Koup RA, Paiardini M, O’Neil SP, McClure HM, Staprans SI, Feinberg MB. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 2003;18:441–52.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Research was supported in part by PHS R01 awards HD032259, AI065265, AI028571, and AI047723; Center for Research for Pediatric Immune Deficiency; Laura McClamma Fellowship, Graduate Alumni Fellowship (SKH), and Stephany W. Holloway University Chair for AIDS Research (MMG); Pediatric Clinical Research Center of All Children’s Hospital and the University of South Florida, and the Maternal Child Health Bureau, R60 MC 00003-01, Department of Health and Human Services, Resources and Services Administration.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John W. Sleasman.

Additional information

Dedication to Dr. Robert A. Good: In many ways the HIV epidemic has defined modern human immunology. Early in the epidemic there was no readily available animal model to study pathogenesis. As a result physicians had to rely on clinical observations to understand disease progression and the factors leading to the development of AIDS. Imagine if Dr. Good’s early work in defining the compartmentalization of adaptive immunity into T and B lymphocytes or his discovery of the important role of the thymus in T cell development had NOT occurred or happened years later? There would have been confusion and frustration in understanding, treating, and controlling this great new plague of mankind. Fortunately Dr. Good’s focus on human immunology as well as his keen ability to make clinical observations and correlate them with functional immunity provided the basis of the future studies that defined the human immune system. Dr. Good and his collaborator’s research facilitated the discovery of CD4 and CD8 T cells and laid the foundation for our understanding T cell homeostasis. Was it pure serendipity that the timeline of the most important human immune deficiency paralleled the great discoveries of human immunology spearheaded by Dr. Robert Good?

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodriguez, C.A., Koch, S., Goodenow, M. et al. Clinical implications of discordant viral and immune outcomes following protease inhibitor containing antiretroviral therapy for HIV-infected children. Immunol Res 40, 271–286 (2008). https://doi.org/10.1007/s12026-007-0031-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-007-0031-1

Keywords

Navigation