Skip to main content

Advertisement

Log in

Immune pathogenesis of pediatric HIV-1 infection

  • Published:
Current HIV/AIDS Reports Aims and scope Submit manuscript

Abstract

Vertical exposure to HIV occurs at a time when functional capacity of the infant‘s immune system is attenuated through immaturity. Immune response capability is rooted in host genetic makeup, and the broad and fine specificity of innate and adaptive immune responses, respectively, shape the outcomes of HIV encounter in some instances and imprint viral changes through selective immune pressure in others. Findings from recent studies have profound implications for understanding immune pathogenesis of pediatric HIV infection and, in particular, highlight the importance of host genetics of both mother and child in determining whether an exposed child acquires HIV infection or not and, if infected, the rate of disease progression. This review focuses on the key host molecules, the CC chemokine CCL3 and HLA, which have taken center stage in these new developments.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Mofenson LM: Advances in the prevention of vertical transmission of human immunodeficiency virus. Semin Pediatr Infect Dis 2003, 14:295–308.

    Article  PubMed  Google Scholar 

  2. Azzoni L, Rutstein RM, Chehimi J, et al.: Dendritic and natural killer cell subsets associated with stable or declining CD4+ cell counts in treated HIV-1-infected children. J Infect Dis 2005, 191:1451–1459.

    Article  PubMed  CAS  Google Scholar 

  3. Mailliard RB, Son YI, Redlinger R, et al.: Dendritic cells mediate NK cell help for Th1 and CTL responses: twosignal requirement for the induction of NK cell helper function. J Immunol 2003, 171:2366–2373.

    PubMed  CAS  Google Scholar 

  4. Fleuridor R, Wilson B, Hou R, et al.: CD1d-restricted natural killer T cells are potent targets for human immunodeficiency virus infection. Immunology 2003, 108:3–9.

    Article  PubMed  CAS  Google Scholar 

  5. Motsinger A, Haas DW, Stanic AK, et al.: CD1d-restricted human natural killer T cells are highly susceptible to human immunodeficiency virus 1 infection. J Exp Med 2002, 195:869–879.

    Article  PubMed  CAS  Google Scholar 

  6. van der Vliet HJ, von Blomberg BM, Hazenberg MD, et al.: Selective decrease in circulating V alpha 24+V beta 11+ NKT cells during HIV type 1 infection. J Immunol 2002, 168:1490–1495.

    PubMed  Google Scholar 

  7. Sandberg JK, Fast NM, Palacios EH, et al.: Selective loss of innate CD4(+) V alpha 24 natural killer T cells in human immunodeficiency virus infection. J Virol 2002, 76:7528–7534.

    Article  PubMed  CAS  Google Scholar 

  8. Scott-Algara D, Buseyne F, Porrot F, et al.: Not all tetramer binding CD8+ T cells can produce cytokines and chemokines involved in the effector functions of virus-specific CD8+ T lymphocytes in HIV-1 infected children. J Clin Immunol 2005, 25:57–67.

    Article  PubMed  CAS  Google Scholar 

  9. Chakraborty R, Morel AS, Sutton JK, et al.: Correlates of delayed disease progression in HIV-1-infected Kenyan children. J Immunol 2005, 174:8191–8199.

    PubMed  CAS  Google Scholar 

  10. Cocchi F, DeVico AL, Garzino-Demo A, et al.: Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995, 270:1811–1815.

    Article  PubMed  CAS  Google Scholar 

  11. Deng H, Liu R, Ellmeier W, et al.: Identification of a major co-receptor for primary isolates of HIV-1. Nature 1996, 381:661–666.

    Article  PubMed  CAS  Google Scholar 

  12. Dragic T, Litwin V, Allaway GP, et al.: HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CCCKR-5. Nature 1996, 381:667–673.

    Article  PubMed  CAS  Google Scholar 

  13. Lehner T, Wang Y, Cranage M, et al.: Protective mucosal immunity elicited by targeted iliac lymph node immunization with a subunit SIV envelope and core vaccine in macaques. Nat Med 1996, 2:767–775.

    Article  PubMed  CAS  Google Scholar 

  14. Heeney JL, Teeuwsen VJ, van Gils M, et al.: Beta-chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques. Proc Natl Acad Sci U S A 1998, 95:10803–10808.

    Article  PubMed  CAS  Google Scholar 

  15. Paxton WA, Martin SR, Tse D, et al.: Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure. Nat Med 1996, 2:412–417.

    Article  PubMed  CAS  Google Scholar 

  16. Zagury D, Lachgar A, Chams V, et al.: C-C chemokines, pivotal in protection against HIV type 1 infection. Proc Natl Acad Sci U S A 1998, 95:3857–3861.

    Article  PubMed  CAS  Google Scholar 

  17. Rosenberg ES, Billingsley JM, Caliendo AM, et al.: Vigorous HIV-1-specific CD4+ T cell responses with control of viremia. Science 1997, 278:1447–1450.

    Article  PubMed  CAS  Google Scholar 

  18. O‘Brien SJ, Nelson GW: Human genes that limit AIDS. Nat Genet 2004, 36:565–574.

    Article  PubMed  CAS  Google Scholar 

  19. Ometto L, Zanotto C, Maccabruni A, et al.: Viral phenotype and host-cell susceptibility to HIV-1 infection as risk factors for mother-to-child HIV-1 transmission. AIDS 1995, 9:427–434.

    PubMed  CAS  Google Scholar 

  20. LaRussa P, Magder LS, Pitt J, et al.: Association of HIV-1 viral phenotype in the MT-2 assay with perinatal HIV transmission. J Acquir Immune Defic Syndr 2002, 30:88–94.

    Article  PubMed  Google Scholar 

  21. Bernstein HB, Kinter AL, Jackson R, Fauci AS: Neonatal natural killer cells produce chemokines and suppress HIV replication in vitro. AIDS Res Hum Retroviruses 2004, 20:1189–1195.

    PubMed  CAS  Google Scholar 

  22. 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, 11:229–234.

    Article  PubMed  CAS  Google Scholar 

  23. Shalekoff S, Tiemessen CT: CCR5 delta32 heterozygosity is associated with an increase in CXCR4 cell surface expression. AIDS Res Hum Retroviruses 2003, 19:531–533.

    Article  PubMed  CAS  Google Scholar 

  24. Wasik TJ, Bratosiewicz J, Wierzbicki A, et al.: Protective role of beta-chemokines associated with HIV-specific Th responses against perinatal HIV transmission. J Immunol 1999, 162:4355–4364.

    PubMed  CAS  Google Scholar 

  25. Menten P, Wuyts A, Van Damme J: Macrophage inflammatory protein-1. Cytokine Growth Factor Rev 2002, 13:455–481.

    Article  PubMed  CAS  Google Scholar 

  26. Gonzalez E, Kulkarni H, Bolivar H, et al.: The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005, 307:1434–1440. A large study of 4309 HIV-positive and HIV-negative individuals of different ancestral origins that found that individuals with fewer CCL3-L1 copies than their population‘s average were more susceptible to HIV infection and rapid disease progression.

    Article  PubMed  CAS  Google Scholar 

  27. Townson JR, Barcellos LF, Nibbs RJ: Gene copy number regulates the production of the human chemokine CCL3-L1. Eur J Immunol 2002, 32:3016–3026.

    Article  PubMed  CAS  Google Scholar 

  28. Matsukawa A, Hogaboam CM, Lukacs NW, Kunkel SL: Chemokines and innate immunity. Rev Immunogenet 2000, 2:339–358.

    PubMed  CAS  Google Scholar 

  29. Tang J, Kaslow RA: The impact of host genetics on HIV infection and disease progression in the era of highly active antiretroviral therapy. AIDS 2003, 17(Suppl 4):S51–60.

    Article  PubMed  Google Scholar 

  30. McMichael A: T cell responses and viral escape. Cell 1998, 93:673–676.

    Article  PubMed  CAS  Google Scholar 

  31. Moore CB, John M, James IR, et al.: Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 2002, 296:1439–1443.

    Article  PubMed  CAS  Google Scholar 

  32. McMichael A, Klenerman P: HIV/AIDS. HLA leaves its footprints on HIV. Science 2002, 296:1410–1411.

    Article  PubMed  CAS  Google Scholar 

  33. Lieberman J: Defying death — HIV mutation to evade cytotoxic T lymphocytes. N Engl J Med 2002, 347:1203–1204.

    Article  PubMed  Google Scholar 

  34. Trachtenberg E, Korber B, Sollars C, et al.: Advantage of rare HLA supertype in HIV disease progression. Nat Med 2003, 9:928–935.

    Article  PubMed  CAS  Google Scholar 

  35. Shearer WT, Quinn TC, LaRussa P, et al.: Viral load and disease progression in infants infected with human immunodeficiency virus type 1. Women and Infants Transmission Study Group. N Engl J Med 1997, 336:1337–1342.

    Article  PubMed  CAS  Google Scholar 

  36. Pliner V, Weedon J, Thomas PA, et al.: Incubation period of HIV-1 in perinatally infected children. New York City Perinatal HIV Transmission Collaborative Study Group. AIDS 1998, 12:759–766.

    Article  PubMed  CAS  Google Scholar 

  37. The European Collaborative Study: Natural history of vertically acquired human immunodeficiency virus-1 infection. Pediatrics 1994, 94:815–819.

    Google Scholar 

  38. Walker BD, Korber BT: Immune control of HIV: the obstacles of HLA and viral diversity. Nat Immunol 2001, 2:473–475.

    Article  PubMed  CAS  Google Scholar 

  39. Nolan D, Gaudieri S, John M, Mallal S: Impact of host genetics on HIV disease progression and treatment: new conflicts on an ancient battleground. AIDS 2004, 18:1231–1240.

    Article  PubMed  CAS  Google Scholar 

  40. Korber B, Gaschen B, Yusim K, et al.: Evolutionary and immunological implications of contemporary HIV-1 variation. Br Med Bull 2001, 58:19–42.

    Article  PubMed  CAS  Google Scholar 

  41. Frederick T, Mascola L, Eller A, et al.: Progression of human immunodeficiency virus disease among infants and children infected perinatally with human immunodeficiency virus or through neonatal blood transfusion. Los Angeles County Pediatric AIDS Consortium and the Los Angeles County-University of Southern California Medical Center and the University of Southern California School of Medicine. Pediatr Infect Dis J 1994, 13:1091–1097.

    Article  PubMed  CAS  Google Scholar 

  42. Goulder PJ, Brander C, Tang Y, et al.: Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 2001, 412:334–338.

    Article  PubMed  CAS  Google Scholar 

  43. Carrington M, Nelson GW, Martin MP, et al.: HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 1999, 283:1748–1752.

    Article  PubMed  CAS  Google Scholar 

  44. Gao X, Nelson GW, Karacki P, et al.: Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N Engl J Med 2001, 344:1668–1675.

    Article  PubMed  CAS  Google Scholar 

  45. Dean M, Carrington M, O‘Brien SJ: Balanced polymorphism selected by genetic versus infectious human disease. Annu Rev Genomics Hum Genet 2002, 3:263–292.

    Article  PubMed  CAS  Google Scholar 

  46. Kuhn L, Abrams EJ, Palumbo P, et al.: Maternal versus paternal inheritance of HLA class I alleles among HIV-infected children: consequences for clinical disease progression. AIDS 2004, 18:1281–1289. A clinical study demonstrating that effects of protective HLA class I alleles are attenuated among children with HIV infection if inherited from their mothers, and that genetic similarity between mother and child is associated with more rapid disease progression in the child.

    Article  PubMed  CAS  Google Scholar 

  47. Friedrich TC, Dodds EJ, Yant LJ, et al.: Reversion of CTL escape-variant immunodeficiency viruses in vivo. Nat Med 2004, 10:275–281.

    Article  PubMed  CAS  Google Scholar 

  48. Leslie AJ, Pfafferott KJ, Chetty P, et al.: HIV evolution: CTL escape mutation and reversion after transmission. Nat Med 2004, 10:282–289.

    Article  PubMed  CAS  Google Scholar 

  49. Feeney ME, Tang Y, Roosevelt KA, et al.: Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLA-B27-positive longterm-nonprogressing child. J Virol 2004, 78:8927–8930.

    Article  PubMed  CAS  Google Scholar 

  50. Kuhn L, Meddows-Taylor S, Gray G, Tiemessen C: Human immunodeficiency virus (HIV)-specific cellular immune responses in newborns exposed to HIV in utero. Clin Infect Dis 2002, 34:267–276.

    Article  PubMed  Google Scholar 

  51. Farquhar C, John-Stewart G: The role of infant immune responses and genetic factors in preventing HIV-1 acquisition and disease progression. Clin Exp Immunol 2003, 134:367–377.

    Article  PubMed  CAS  Google Scholar 

  52. Kuhn L, Coutsoudis A, Moodley D, et al.: T-helper cell responses to HIV envelope peptides in cord blood: protection against intrapartum and breast-feeding transmission. AIDS 2001, 15:1–9.

    Article  PubMed  CAS  Google Scholar 

  53. Kuhn L, Meddows-Taylor S, Gray G, et al.: Reduced HIVstimulated T-helper cell reactivity in cord blood with short-course antiretroviral treatment for prevention of maternal-infant transmission. Clin Exp Immunol 2001, 123:443–450.

    Article  PubMed  CAS  Google Scholar 

  54. MacDonald KS, Embree J, Njenga S, et al.: Mother-child class I HLA concordance increases perinatal human immunodeficiency virus type 1 transmission. J Infect Dis 1998, 177:551–556.

    Article  PubMed  CAS  Google Scholar 

  55. Kiepiela P, Leslie AJ, Honeyborne I, et al.: Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 2004, 432:769–775.

    Article  PubMed  CAS  Google Scholar 

  56. Farquhar C, Rowland-Jones S, Mbori-Ngacha D, et al.: Human leukocyte antigen (HLA) B*18 and protection against mother-to-child HIV type 1 transmission. AIDS Res Hum Retroviruses 2004, 20:692–697.

    Article  PubMed  CAS  Google Scholar 

  57. Winchester R, Pitt J, Charurat M, et al.: Mother-to-child transmission of HIV-1: strong association with certain maternal HLA-B alleles independent of viral load implicates innate immune mechanisms. J Acquir Immune Defic Syndr 2004, 36:659–670. Large study of associations between HLA-B alleles and MTCT identifying an importance role for certain maternal HLA polymorphisms in recognition of NK cell receptors that may explain protection against transmission through interrelated adaptive and innate immune mechanisms.

    Article  PubMed  Google Scholar 

  58. Martin MP, Gao X, Lee JH, et al.: Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 2002, 31:429–434.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Caroline T. Tiemessen PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tiemessen, C.T., Kuhn, L. Immune pathogenesis of pediatric HIV-1 infection. Curr HIV/AIDS Rep 3, 13–19 (2006). https://doi.org/10.1007/s11904-006-0003-4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11904-006-0003-4

Keywords

Navigation