Current HIV/AIDS Reports

, Volume 11, Issue 1, pp 1–10

Are Infants Unique in Their Ability to be “Functionally Cured” of HIV-1?

HIV Pathogenesis and Treatment (AL Landay, Section Editor)

Abstract

The recent report of an infant that appears to have achieved a “functional cure” of HIV-1 following receipt of antiretroviral therapy (ART) within 30 hours of birth raises many questions: was the child infected? Was this result due to unique features of this particular infant’s immune system, the immune system of infants or the very early initiation of effective ART? In this manuscript, we discuss the pathogenesis of HIV-1 in infants, highlighting the unique features of infant immune development and how these may inform efforts to cure HIV infection. We will also compare the path to infant “cure” to cures in adults.

Keywords

HIV Mother-to-child transmission (MTCT) Neonate Infant Pathogenesis Cure CD4+ T cells CD8+ T cells Central memory T cells (TCMEffector memory T cells (TEMReservoir Immune quiescence Immune tolerance Microbial translocation Functional cure HIV-1 Antiretroviral therapy (ART) HIV pathogenesis 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Persaud D, Gay H, Ziemniak C, Chen YH, Paitak M, Chun TW et al. Absence of Detectable HIV-1 Viremia after Treatment Cessation in an Infant. N Engl J Med. 2013;369(19):1828–35. doi:10.1056/NEJMoa1302976.Google Scholar
  2. 2.
    Rates of mother-to-child transmission of HIV-1 in Africa, America, and Europe: results from 13 perinatal studies. The Working Group on Mother-To-Child Transmission of HIV. J Acquir Immune Defic Syndr Hum Retrovirol: Off Publ Int Retrovirol Assoc. 1995;8(5):506–10.Google Scholar
  3. 3.
    Taha TE, James MM, Hoover DR, Sun J, Laeyendecker O, Mullis CE, et al. Association of recent HIV infection and in-utero HIV-1 transmission. AIDS. 2011;25(11):1357–64. doi:10.1097/QAD.0b013e3283489d45.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003;112(5):973–80. doi:10.1016/j.jaci.2003.07.003.PubMedCrossRefGoogle Scholar
  5. 5.
    Schatorje EJ, Gemen EF, Driessen GJ, Leuvenink J, van Hout RW, de Vries E. Paediatric reference values for the peripheral T cell compartment. Scand J Immunol. 2012;75(4):436–44. doi:10.1111/j.1365-3083.2012.02671.x.PubMedCrossRefGoogle Scholar
  6. 6.
    Shalekoff S, Gray GE, Tiemessen CT. Age-related changes in expression of CXCR4 and CCR5 on peripheral blood leukocytes from uninfected infants born to human immunodeficiency virus type 1-infected mothers. Clin Diagn Lab Immunol. 2004;11(1):229–34.PubMedCentralPubMedGoogle Scholar
  7. 7.••
    Bunders MJ, van der Loos CM, Klarenbeek PL, van Hamme JL, Boer K, Wilde JC, et al. Memory CD4(+)CCR5(+) T cells are abundantly present in the gut of newborn infants to facilitate mother-to-child transmission of HIV-1. Blood. 2012;120(22):4383–90. doi:10.1182/blood-2012-06-437566. This recent article establishes that there is a large subset of mucosal memory CD4+CCR5+ T-cells with predominantly a Th1 and Th17 phenotype present in fetal and infant gut mucosa. Google Scholar
  8. 8.
    Auewarakul P, Sangsiriwut K, Pattanapanyasat K, Wasi C, Lee TH. Age-dependent expression of the HIV-1 coreceptor CCR5 on CD4+ lymphocytes in children. J Acquir Immune Defic Syndr. 2000;24(3):285–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Bradley LM, Bradley JS, Ching DL, Shiigi SM. Predominance of T cells that express CD45R in the CD4+ helper/inducer lymphocyte subset of neonates. Clin Immunol Immunopathol. 1989;51(3):426–35.PubMedCrossRefGoogle Scholar
  10. 10.
    Berry SM, Fine N, Bichalski JA, Cotton DB, Dombrowski MP, Kaplan J. Circulating lymphocyte subsets in second- and third-trimester fetuses: comparison with newborns and adults. Am J Obstet Gynecol. 1992;167(4 Pt 1):895–900.PubMedCrossRefGoogle Scholar
  11. 11.
    Clement LT, Vink PE, Bradley GE. Novel immunoregulatory functions of phenotypically distinct subpopulations of CD4+ cells in the human neonate. J Immunol. 1990;145(1):102–8.PubMedGoogle Scholar
  12. 12.
    Ho WZ, Lioy J, Song L, Cutilli JR, Polin RA, Douglas SD. Infection of cord blood monocyte-derived macrophages with human immunodeficiency virus type 1. J Virol. 1992;66(1):573–9.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Reinhardt PP, Reinhardt B, Lathey JL, Spector SA. Human cord blood mononuclear cells are preferentially infected by non-syncytium-inducing, macrophage-tropic human immunodeficiency virus type 1 isolates. J Clin Microbiol. 1995;33(2):292–7.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Sundaravaradan V, Saxena SK, Ramakrishnan R, Yedavalli VR, Harris DT, Ahmad N. Differential HIV-1 replication in neonatal and adult blood mononuclear cells is influenced at the level of HIV-1 gene expression. Proc Natl Acad Sci U S A. 2006;103(31):11701–6. doi:10.1073/pnas.0602185103.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Tugizov SM, Herrera R, Veluppillai P, Greenspan D, Soros V, Greene WC, et al. Differential transmission of HIV traversing fetal oral/intestinal epithelia and adult oral epithelia. J Virol. 2012;86(5):2556–70. doi:10.1128/JVI.06578-11.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Lucivero G, Surico G, Mazzini G, Dell’Osso A, Bonomo L. Age-related changes in the proliferative kinetics of phytohemagglutinin-stimulated lymphocytes. Analysis by uptake of tritiated precursors of DNA, RNA and proteins, and by flow cytometry. Mech Ageing Dev. 1988;43(3):259–67.PubMedCrossRefGoogle Scholar
  17. 17.
    Krogstad PA, Zack JA, Chen IS. HIV-1 reverse transcription in cord blood lymphocytes: implications for infection of newborns. AIDS Res Hum Retroviruses. 1994;10(2):143–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Sperduto AR, Bryson YJ, Chen IS. Increased susceptibility of neonatal monocyte/macrophages to HIV-1 infection. AIDS Res Hum Retroviruses. 1993;9(12):1277–85.PubMedCrossRefGoogle Scholar
  19. 19.
    Hariharan D, Ho W, Cutilli J, Campbell DE, Douglas SD. C-C chemokine profile of cord blood mononuclear cells: selective defect in RANTES production. Blood. 2000;95(2):715–8.PubMedGoogle Scholar
  20. 20.
    Yang LP, Riley JL, Carroll RG, June CH, Hoxie J, Patterson BK, et al. Productive infection of neonatal CD8+ T lymphocytes by HIV-1. J Exp Med. 1998;187(7):1139–44.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.••
    Mold JE, Venkatasubrahmanyam S, Burt TD, Michaelsson J, Rivera JM, Galkina SA, et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science. 2010;330(6011):1695–9. doi:10.1126/science.1196509. This article provides evidence that fetal and adult T cells are distinct populations that arise from different populations of hematopoietic stem cells that are present at different stages of development. Additionally, evidence is provided that fetal T cells are biased towards immune tolerance Google Scholar
  22. 22.
    Mold JE, McCune JM. At the crossroads between tolerance and aggression: revisiting the “layered immune system” hypothesis. Chimerism. 2011;2(2):35–41. doi:10.4161/chim.2.2.16329.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Prendergast AJ, Klenerman P, Goulder PJ. The impact of differential antiviral immunity in children and adults. Nat Rev Immunol. 2012;12(9):636–48. doi:10.1038/nri3277.PubMedCrossRefGoogle Scholar
  24. 24.
    Michaelsson J, Mold JE, McCune JM, Nixon DF. Regulation of T cell responses in the developing human fetus. J Immunol. 2006;176(10):5741–8.PubMedGoogle Scholar
  25. 25.
    Mold JE, Michaelsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science. 2008;322(5907):1562–5. doi:10.1126/science.1164511.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Ladd M, Sharma A, Huang Q, Wang AY, Xu L, Genowati I, et al. Natural killer T cells constitutively expressing the interleukin-2 receptor alpha chain early in life are primed to respond to lower antigenic stimulation. Immunology. 2010;131(2):289–99. doi:10.1111/j.1365-2567.2010.03304.x.PubMedCrossRefGoogle Scholar
  27. 27.
    Kollmann TR, Levy O, Montgomery RR, Goriely S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity. 2012;37(5):771–83. doi:10.1016/j.immuni.2012.10.014.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Legrand FA, Nixon DF, Loo CP, Ono E, Chapman JM, Miyamoto M, et al. Strong HIV-1-specific T cell responses in HIV-1-exposed uninfected infants and neonates revealed after regulatory T cell removal. PloS one. 2006;1:e102. doi:10.1371/journal.pone.0000102.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990;61(2):213–22.PubMedCrossRefGoogle Scholar
  30. 30.
    Stiehm ER, Fudenberg HH. Serum levels of immune globulins in health and disease: a survey. Pediatrics. 1966;37(5):715–27.PubMedGoogle Scholar
  31. 31.
    Siegrist CA, Aspinall R. B-cell responses to vaccination at the extremes of age. Nat Rev Immunol. 2009;9(3):185–94. doi:10.1038/nri2508.PubMedCrossRefGoogle Scholar
  32. 32.
    Siegrist CA. Mechanisms by which maternal antibodies influence infant vaccine responses: review of hypotheses and definition of main determinants. Vaccine. 2003;21(24):3406–12.PubMedCrossRefGoogle Scholar
  33. 33.
    Zinkernagel RM. Maternal antibodies, childhood infections, and autoimmune diseases. N Engl J Med. 2001;345(18):1331–5. doi:10.1056/NEJMra012493.
  34. 34.
    Luzuriaga K, Chen YH, Ziemniak C, Siberry G, Strain M, Richman D et al. Absent HIV-specific Immune Responses and Replication-competent HIV Reservoirs in Perinatally Infected Youth Treated from Infancy: Towards Cure. 20th Conference on Retroviruses and Opportunistic Infections Atlanta, GA2013.Google Scholar
  35. 35.
    Yukl SA, Boritz E, Busch M, Bentsen C, Chun TW, Douek D, et al. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS pathogens. 2013;9(5):e1003347. doi:10.1371/journal.ppat.1003347.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.••
    Henrich TJ, Hu Z, Li JZ, Sciaranghella G, Busch MP, Keating SM, et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis. 2013;207(11):1694–702. doi:10.1093/infdis/jit086. This article describes the long-term reduction in reservoirs of HIV-1 following reduced-intensity conditioning allogeneic stem cell transplantation of “Patient A and B” before ART was interrupted.
  37. 37.
    Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998;280(5362):427–31.PubMedCrossRefGoogle Scholar
  38. 38.
    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(6):761–70. doi:10.1084/jem.20041196.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    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(6):749–59. doi:10.1084/jem.20040874.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Levesque MC, Moody MA, Hwang KK, Marshall DJ, Whitesides JF, Amos JD, et al. Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection. PLoS Med. 2009;6(7):e1000107. doi:10.1371/journal.pmed.1000107.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    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(12):e484. doi:10.1371/journal.pmed.0030484.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Klatt NR, Chomont N, Douek DC, Deeks SG. Immune activation and HIV persistence: implications for curative approaches to HIV infection. Immunol Rev. 2013;254(1):326–42. doi:10.1111/imr.12065.PubMedCrossRefGoogle Scholar
  43. 43.
    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(12):1365–71. doi:10.1038/nm1511.PubMedCrossRefGoogle Scholar
  44. 44.
    Abel K, Pahar B, Van Rompay KK, Fritts L, Sin C, Schmidt K, et al. Rapid virus dissemination in infant macaques after oral simian immunodeficiency virus exposure in the presence of local innate immune responses. J Virol. 2006;80(13):6357–67. doi:10.1128/JVI.02240-05.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Tobin NH, Aldrovandi GM. Immunology of pediatric HIV infection. Immunol Rev. 2013;254(1):143–69. doi:10.1111/imr.12074.PubMedCrossRefGoogle Scholar
  46. 46.
    Nanthakumar N, Meng D, Goldstein AM, Zhu W, Lu L, Uauy R, et al. The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response. PloS one. 2011;6(3):e17776. doi:10.1371/journal.pone.0017776.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Claud EC, Lu L, Anton PM, Savidge T, Walker WA, Cherayil BJ. Developmentally regulated IkappaB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc Natl Acad Sci U S A. 2004;101(19):7404–8. doi:10.1073/pnas.0401710101.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA. Inflammation in the developing human intestine: a possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci U S A. 2000;97(11):6043–8.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Fawzi W, Msamanga G, Renjifo B, Spiegelman D, Urassa E, Hashemi L, et al. Predictors of intrauterine and intrapartum transmission of HIV-1 among Tanzanian women. AIDS. 2001;15(9):1157–65.PubMedCrossRefGoogle Scholar
  50. 50.
    Insoft RM, Sanderson IR, Walker WA. Development of immune function in the intestine and its role in neonatal diseases. Pediatr Clin North Am. 1996;43(2):551–71.PubMedCrossRefGoogle Scholar
  51. 51.
    Papasavvas E, Azzoni L, Foulkes A, Violari A, Cotton MF, Pistilli M, et al. Increased microbial translocation in </= 180 days old perinatally human immunodeficiency virus-positive infants as compared with human immunodeficiency virus-exposed uninfected infants of similar age. Pediatr Infect Dis J. 2011;30(10):877–82. doi:10.1097/INF.0b013e31821d141e.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Wallet MA, Rodriguez CA, Yin L, Saporta S, Chinratanapisit S, Hou W, et al. Microbial translocation induces persistent macrophage activation unrelated to HIV-1 levels or T-cell activation following therapy. AIDS. 2010;24(9):1281–90. doi:10.1097/QAD.0b013e328339e228.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Levy O. Innate immunity of the human newborn: distinct cytokine responses to LPS and other Toll-like receptor agonists. J Endotoxin Res. 2005;11(2):113–6. doi:10.1179/096805105X37376.PubMedCrossRefGoogle Scholar
  54. 54.
    Mayaux MJ, Burgard M, Teglas JP, Cottalorda J, Krivine A, Simon F, et al. Neonatal characteristics in rapidly progressive perinatally acquired HIV-1 disease. The French Pediatric HIV Infection Study Group. JAMA: the journal of the American Medical Association. 1996;275(8):606–10.CrossRefGoogle Scholar
  55. 55.
    Becquet R, Marston M, Dabis F, Moulton LH, Gray G, Coovadia HM, et al. Children who acquire HIV infection perinatally are at higher risk of early death than those acquiring infection through breastmilk: a meta-analysis. PloS one. 2012;7(2):e28510. doi:10.1371/journal.pone.0028510.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Mphatswe W, Blanckenberg N, Tudor-Williams G, Prendergast A, Thobakgale C, Mkhwanazi N, et al. High frequency of rapid immunological progression in African infants infected in the era of perinatal HIV prophylaxis. AIDS. 2007;21(10):1253–61. doi:10.1097/QAD.0b013e3281a3bec2.PubMedCrossRefGoogle Scholar
  57. 57.
    Level and pattern of HIV-1-RNA viral load over age: differences between girls and boys? AIDS. 2002;16(1):97–104.Google Scholar
  58. 58.
    Dunn D. Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis. Lancet. 2003;362(9396):1605–11.PubMedCrossRefGoogle Scholar
  59. 59.
    McIntosh K, Shevitz A, Zaknun D, Kornegay J, Chatis P, Karthas N, et al. Age- and time-related changes in extracellular viral load in children vertically infected by human immunodeficiency virus. Pediatr Infect Dis J. 1996;15(12):1087–91.PubMedCrossRefGoogle Scholar
  60. 60.••
    Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360(7):692–8. doi:10.1056/NEJMoa0802905. This case report describes the first known cure of HIV-1, the “Berlin” patient, by CCR5 Delta32/Delta32 stem-cell transplantation. Google Scholar
  61. 61.
    Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, et al. Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood. 2011;117(10):2791–9. doi:10.1182/blood-2010-09-309591.PubMedCrossRefGoogle Scholar
  62. 62.
    Henrich T, Hanhauser E, Sirignano M, Davis B, Lee T-H, Keating S et al. In depth investigation of peripheral and gut HIV-1 reservoirs, HIV-specific cellular immunity, and host microchimerism following allogeneic hematopoetic stem cell transplantation. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; Kuala Lumpur, Malaysia2013.Google Scholar
  63. 63.
    Baur A, Schwarz N, Ellinger S, Korn K, Harrer T, Mang K, et al. Continuous clearance of HIV in a vertically infected child. Lancet. 1989;2(8670):1045.PubMedCrossRefGoogle Scholar
  64. 64.
    Roques PA, Gras G, Parnet-Mathieu F, Mabondzo AM, Dollfus C, Narwa R, et al. Clearance of HIV infection in 12 perinatally infected children: clinical, virological and immunological data. AIDS. 1995;9(12):F19–26.PubMedGoogle Scholar
  65. 65.
    Bakshi SS, Tetali S, Abrams EJ, Paul MO, Pahwa SG. Repeatedly positive human immunodeficiency virus type 1 DNA polymerase chain reaction in human immunodeficiency virus-exposed seroreverting infants. Pediatr Infect Dis J. 1995;14(8):658–62.PubMedCrossRefGoogle Scholar
  66. 66.
    Newell ML, Dunn D, De Maria A, Ferrazin A, De Rossi A, Giaquinto C, et al. Detection of virus in vertically exposed HIV-antibody-negative children. Lancet. 1996;347(8996):213–5.PubMedCrossRefGoogle Scholar
  67. 67.
    Bryson YJ, Pang S, Wei LS, Dickover R, Diagne A, Chen IS. Clearance of HIV infection in a perinatally infected infant. N Engl J Med. 1995;332(13):833–8. doi:10.1056/NEJM199503303321301.Google Scholar
  68. 68.
    Frenkel LM, Mullins JI, Learn GH, Manns-Arcuino L, Herring BL, Kalish ML, et al. Genetic evaluation of suspected cases of transient HIV-1 infection of infants. Science. 1998;280(5366):1073–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Bryson YJ, Luzuriaga K, Sullivan JL, Wara DW. Proposed definitions for in utero versus intrapartum transmission of HIV-1. N Engl J Med. 1992;327(17):1246–7. doi:10.1056/NEJM199210223271718.Google Scholar
  70. 70.
    Rouzioux C, Costagliola D, Burgard M, Blanche S, Mayaux MJ, Griscelli C, et al. Estimated timing of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission by use of a Markov model. The HIV Infection in Newborns French Collaborative Study Group. American journal of epidemiology. 1995;142(12):1330–7.PubMedGoogle Scholar
  71. 71.
    Lallemant M, Jourdain G, Le Coeur S, Kim S, Koetsawang S, Comeau AM, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand) Investigators. N Engl J Med. 2000;343(14):982–91.Google Scholar
  72. 72.
    Kourtis AP, Bulterys M, Nesheim SR, Lee FK. Understanding the timing of HIV transmission from mother to infant. JAMA : the journal of the American Medical Association. 2001;285(6):709–12.CrossRefGoogle Scholar
  73. 73.•
    Micek MA, Blanco AJ, Beck IA, Dross S, Matunha L, Montoya P, et al. Nevirapine resistance by timing of HIV type 1 infection in infants treated with single-dose nevirapine. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2010;50(10):1405–14. doi:10.1086/652151. This prospective, observation cohort study suggests that the composition of the latent reservoir in perinatally infected infants depends on the timing of infant infection. In infants whose mothers received single dose nevirapine during delivery, infants infected in utero were more likely have wild-type viruses in their long-term reservoir whereas infants infected peripartum were more likely to have nevirapine-resistant viral variants in their long-term reservoir.
  74. 74.
    Nielsen-Saines K, Bryson Y, Watts DH, Veloso VG, Bethel J, Xu J et al. HIV-1 viral kinetics among in utero and intrapartum-infected infants in NICHD HPTN 040/ PACTG 1043. 19th International AIDS Conference; Washington, D.C.2012.Google Scholar
  75. 75.••
    Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS pathogens. 2013;9(3):e1003211. doi:10.1371/journal.ppat.1003211. This article shows that early initiated antiretroviral therapy can increase the number of subjects that achieve post-treatment HIV-1 control from 1% to approximately 15%. The study carefully compares and contrasts the characteristics of post-treatment controllers (PTC) and HIV-immune controllers (HIC).
  76. 76.
    Saez-Cirion A, Pancino G. HIV controllers: a genetically determined or inducible phenotype? Immunol Rev. 2013;254(1):281–94. doi:10.1111/imr.12076.PubMedCrossRefGoogle Scholar
  77. 77.
    Hocqueloux L, Prazuck T, Avettand-Fenoel V, Lafeuillade A, Cardon B, Viard JP, et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS. 2010;24(10):1598–601.PubMedCrossRefGoogle Scholar
  78. 78.
    Persaud D, Pierson T, Ruff C, Finzi D, Chadwick KR, Margolick JB, et al. A stable latent reservoir for HIV-1 in resting CD4(+) T lymphocytes in infected children. J Clin Invest. 2000;105(7):995–1003. doi:10.1172/JCI9006.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Ruff CT, Ray SC, Kwon P, Zinn R, Pendleton A, Hutton N, et al. Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pediatric patients with extensive antiretroviral exposure. J Virol. 2002;76(18):9481–92.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.•
    Persaud D, Palumbo PE, Ziemniak C, Hughes MD, Alvero CG, Luzuriaga K, et al. Dynamics of the resting CD4(+) T-cell latent HIV reservoir in infants initiating HAART less than 6 months of age. AIDS. 2012;26(12):1483–90. doi:10.1097/QAD.0b013e3283553638. This study evaluates the dynamics of the resting CD4+ T-cell reservoir in infants receiving ART within 6 months of life. Importantly, it demonstrates that the size of the latent reservoir correlates with the time to the first undetectable viral load.
  81. 81.
    Archin NM, Vaidya NK, Kuruc JD, Liberty AL, Wiegand A, Kearney MF, et al. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci U S A. 2012;109(24):9523–8. doi:10.1073/pnas.1120248109.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Blankson JN, Persaud D, Siliciano RF. The challenge of viral reservoirs in HIV-1 infection. Annu Rev Med. 2002;53:557–93. doi:10.1146/annurev.med.53.082901.104024.PubMedCrossRefGoogle Scholar
  83. 83.
    Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5(5):512–7. doi:10.1038/8394.PubMedCrossRefGoogle Scholar
  84. 84.
    Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278(5341):1295–300.PubMedCrossRefGoogle Scholar
  85. 85.
    Holte SE, Melvin AJ, Mullins JI, Tobin NH, Frenkel LM. Density-dependent decay in HIV-1 dynamics. J Acquir Immune Defic Syndr. 2006;41(3):266–76. doi:10.1097/01.qai.0000199233.69457.e4.PubMedCrossRefGoogle Scholar
  86. 86.
    Ramratnam B, Mittler JE, Zhang L, Boden D, Hurley A, Fang F, et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nat Med. 2000;6(1):82–5. doi:10.1038/71577.PubMedCrossRefGoogle Scholar
  87. 87.
    Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003;9(6):727–8. doi:10.1038/nm880.PubMedCrossRefGoogle Scholar
  88. 88.••
    Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15(8):893–900. doi:10.1038/nm.1972. This article identifies that central memory and transitional memory CD4+ T-cells are the major cellular reservoirs of HIV-1and that viral persistence is ensured by T cell survival in the former reservoir and homeostatic proliferation in the latter reservoir. Google Scholar
  89. 89.
    Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, et al. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol. 2012;12(8):607–14. doi:10.1038/nri3262.PubMedCrossRefGoogle Scholar
  90. 90.•
    Mueller SN, Gebhardt T, Carbone FR, Heath WR. Memory T cell subsets, migration patterns, and tissue residence. Annu Rev Immunol. 2013;31:137–61. doi:10.1146/annurev-immunol-032712-095954. This important study characterizes early immunologic and virologic events in the peripheral blood and gut of individuals treated during primary HIV infection. The study demonstrates that earlier treatment limits the size of the viral reservoir and the long-term depletion of CD4+CCR5+ T-cells in the gut. Further studies of this cohort, presented at CROI 2013 demonstrate that not only the size, but which CD4+ T-cell subsets get seeded changes with timing of initiation of ART.
  91. 91.
    Haase AT. Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med. 2011;62:127–39. doi:10.1146/annurev-med-080709-124959.PubMedCrossRefGoogle Scholar
  92. 92.•
    Ananworanich J, Schuetz A, Vandergeeten C, Sereti I, de Souza M, Rerknimitr R, et al. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PloS one. 2012;7(3):e33948. doi:10.1371/journal.pone.0033948. This important study characterizes early immunologic and virologic events in the peripheral blood and gut of individuals treated during primary HIV infection. The study demonstrates that earlier treatment limits the size of the viral reservoir and the long-term depletion of CD4+CCR5+ T-cells in the gut. Further studies of this cohort, presented at CROI 2013 demonstrate that not only the size, but which CD4+ T-cell subsets get seeded changes with timing of initiation of ART.
  93. 93.
    Ananworanich J, Vandergeeten C, Chomchey N, Phanuphak N, Ngauy V, Sekaly R-P et al. Early ART Intervention Restricts the Seeding of the HIV Reservoir in Long-lived Central Memory CD4 T Cells. 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, GA2013.Google Scholar
  94. 94.
    Chomont N, DaFonseca S, Vandergeeten C, Ancuta P, Sekaly RP. Maintenance of CD4+ T-cell memory and HIV persistence: keeping memory, keeping HIV. Curr Opin HIV AIDS. 2011;6(1):30–6. doi:10.1097/COH.0b013e3283413775.PubMedCrossRefGoogle Scholar
  95. 95.
    Goga AE, Dinh TH, Jackson D, group ftSs. Impact of the national prevention of mother-to-child transmission of HIV (PMTCT) program on perinatal mother-to-child transmission of HIV (MTCT) measured at six weeks postpartum, South Africa (SA). XIX International AIDS Conference; Washington2012.Google Scholar
  96. 96.
    Mid-year Population Estimates 2011. South Africa; Statistics South Africa2011.Google Scholar
  97. 97.
    Moodley D, Esterhuizen TM, Pather T, Chetty V, Ngaleka L. High HIV incidence during pregnancy: compelling reason for repeat HIV testing. AIDS. 2009;23(10):1255–9. doi:10.1097/QAD.0b013e32832a5934.PubMedCrossRefGoogle Scholar
  98. 98.
    Organization WH. Guidance on global scale-up of the prevention of mother-to-child transmission of HIV. 2007. http://www.who.int/hiv/pub/guidelines/pmtct_scaleup2007/en/index.html.

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of PediatricsChildren’s Hospital Los AngelesLos AngelesUSA
  2. 2.Department of Pediatrics, Children’s Hospital Los AngelesThe Saban Research Institute, University of Southern CaliforniaLos AngelesUSA

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