The Immune System of HIV-Exposed Uninfected Infants

Bahaa Abu-Raya, Tobias R Kollmann, Arnaud Marchant, Duncan M MacGillivray, Bahaa Abu-Raya, Tobias R Kollmann, Arnaud Marchant, Duncan M MacGillivray

Abstract

Infants born to human immunodeficiency virus (HIV) infected women are HIV-exposed but the majority remains uninfected [i.e., HIV-exposed uninfected (HEU)]. HEU infants suffer greater morbidity and mortality from infections compared to HIV-unexposed (HU) peers. The reason(s) for these worse outcomes are uncertain, but could be related to an altered immune system state. This review comprehensively summarizes the current literature investigating the adaptive and innate immune system of HEU infants. HEU infants have altered cell-mediated immunity, including impaired T-cell maturation with documented hypo- as well as hyper-responsiveness to T-cell activation. And although prevaccination vaccine-specific antibody levels are often lower in HEU than HU, most HEU infants mount adequate humoral immune response following primary vaccination with diphtheria toxoid, haemophilus influenzae type b, whole cell pertussis, measles, hepatitis B, tetanus toxoid, and pneumococcal conjugate vaccines. However, HEU infants are often found to have lower absolute neutrophil counts as compared to HU infants. On the other hand, an increase of innate immune cytokine production and expression of co-stimulatory markers has been noted in HEU infants, but this increase appears to be restricted to the first few weeks of life. The immune system of HEU children beyond infancy remains largely unexplored.

Keywords: HIV; HIV-exposed infants; cell-mediated immune system; humoral immune response; innate immune system.

References

    1. John GC, Kreiss J. Mother-to-child transmission of human immunodeficiency virus type 1. Epidemiol Rev (1996) 18(2):149–57.10.1093/oxfordjournals.epirev.a017922
    1. Burns DN, Mofenson LM. Pediatric HIV-1 infection. Lancet (1999) 354(Suppl 2):SII1–6.10.1016/S0140-6736(99)90249-0
    1. Kind C, Rudin C, Siegrist CA, Wyler CA, Biedermann K, Lauper U, et al. Prevention of vertical HIV transmission: additive protective effect of elective Cesarean section and zidovudine prophylaxis. AIDS (1998) 12:205–10.10.1097/00002030-199802000-00011
    1. European Collaborative Study. Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy. Clin Infect Dis (2005) 40:458–65.10.1086/427287
    1. Chasela CS, Hudgens MG, Jamieson DJ, Kayira D, Hosseinipour MC, Kourtis AP, et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med (2010) 362(24):2271–81.10.1056/NEJMoa0911486
    1. Shapiro RL, Hughes MD, Ogwu A, Kitch D, Lockman S, Moffat C, et al. Antiretroviral regimens in pregnancy and breast feeding in Botswana. N Engl J Med (2010) 362(24):2282–94.10.1056/NEJMoa0907736
    1. Marinda E, Humphrey JH, Iliff PJ, Mutasa K, Nathoo KJ, Piwoz EG, et al. Child mortality according to maternal and infant HIV status in Zimbabwe. Pediatr Infect Dis J (2007) 26(6):519–26.10.1097/01.inf.0000264527.69954.4c
    1. Kuhn L, Kasonde P, Sinkala M, Kankasa C, Semrau K, Scott N, et al. Does severity of HIV disease in HIV-infected mothers affect mortality and morbidity among their uninfected infants? Clin Infect Dis (2005) 41(11):1654–61.10.1086/498029
    1. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F, et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet (2004) 364(9441):1236–43.10.1016/S0140-6736(04)17140-7
    1. Filteau S. The HIV-exposed, uninfected African child. Trop Med Int Health (2009) 14(3):276–87.10.1111/j.1365-3156.2009.02220.x
    1. Singh HK, Gupte N, Kinikar A, Bharadwaj R, Sastry J, Suryavanshi N, et al. High rates of all-cause and gastroenteritis-related hospitalization morbidity and mortality among HIV-exposed Indian infants. BMC Infect Dis (2011) 11:193.10.1186/1471-2334-11-193
    1. Epalza C, Goetghebuer T, Hainaut M, Prayez F, Barlow P, Dediste A, et al. High incidence of invasive group B streptococcal infections in HIV-exposed uninfected infants. Pediatrics (2010) 126(3):e631–8.10.1542/peds.2010-0183
    1. Kuhn L, Thea DM, Aldrovandi GM. Bystander effects: children who escape infection but not harm. J Acquir Immune Defic Syndr (2007) 46(5):517–8.10.1097/QAI.0b013e31814d6600
    1. Mussi-Pinhata MM, Motta F, Freimanis-Hance L, de Souza R, Szyld E, Succi RC, et al. Lower respiratory tract infections among human immunodeficiency virus-exposed, uninfected infants. Int J Infect Dis (2010) 14(Suppl 3):e176–82.10.1016/j.ijid.2010.01.006
    1. Koyanagi A, Humphrey JH, Ntozini R, Nathoo K, Moulton LH, Iliff P, et al. Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virus-infected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy. Pediatr Infect Dis J (2011) 30(1):45–51.10.1097/INF.0b013e3181ecbf7e
    1. McNally LM, Jeena PM, Gajee K, Thula SA, Sturm AW, Cassol S, et al. Effect of age, polymicrobial disease, and maternal HIV status on treatment response and cause of severe pneumonia in South African children: a prospective descriptive study. Lancet (2007) 369(9571):1440–51.10.1016/S0140-6736(07)60670-9
    1. Fawzy A, Arpadi S, Kankasa C, Sinkala M, Mwiya M, Thea DM, et al. Early weaning increases diarrhea morbidity and mortality among uninfected children born to HIV-infected mothers in Zambia. J Infect Dis (2011) 203(9):1222–30.10.1093/infdis/jir019
    1. Slogrove A, Reikie B, Naidoo S, De Beer C, Ho K, Cotton M, et al. HIV-exposed uninfected infants are at increased risk for severe infections in the first year of life. J Trop Pediatr (2012) 58(6):505–8.10.1093/tropej/fms019
    1. Adler C, Haelterman E, Barlow P, Marchant A, Levy J, Goetghebuer T. Severe infections in HIV-exposed uninfected infants born in a European country. PLoS One (2015) 10(8):e0135375.10.1371/journal.pone.0135375
    1. Mussi-Pinhata MM, Freimanis L, Yamamoto AY, Korelitz J, Pinto JA, Cruz ML, et al. Infectious disease morbidity among young HIV-1-exposed but uninfected infants in Latin American and Caribbean countries: the National Institute of Child Health and Human Development International Site Development Initiative Perinatal Study. Pediatrics (2007) 119(3):e694–704.10.1542/peds.2006-1856
    1. Afran L, Garcia Knight M, Nduati E, Urban BC, Heyderman RS, Rowland-Jones SL. HIV-exposed uninfected children: a growing population with a vulnerable immune system?: HEU children: a vulnerable immune system? Clin Exp Immunol (2014) 176(1):11–22.10.1111/cei.12251
    1. Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS (1998) 12(14):1735–44.10.1097/00002030-199814000-00004
    1. Venhoff N, Walker UA. Mitochondrial disease in the offspring as a result of antiretroviral therapy. Expert Opin Drug Saf (2006) 5(3):373–81.10.1517/14740338.5.3.373
    1. Foster C, Lyall H. HIV and mitochondrial toxicity in children. J Antimicrob Chemother (2008) 61(1):8–12.10.1093/jac/dkm411
    1. Scruggs ER, Dirks Naylor AJ. Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy. Pharmacology (2008) 82(2):83–8.10.1159/000134943
    1. Yamaguchi T, Katoh I, Kurata S. Azidothymidine causes functional and structural destruction of mitochondria, glutathione deficiency and HIV-1 promoter sensitization: AZT causes mitochondrial dysfunction. Eur J Biochem (2002) 269(11):2782–8.10.1046/j.1432-1033.2002.02954.x
    1. Dainiak N, Worthington M, Riordan MA, Kreczko S, Goldman L. 3′-Azido-3′-deoxythymidine (AZT) inhibits proliferation in vitro of human haematopoietic progenitor cells. Br J Haematol (1988) 69(3):299–304.10.1111/j.1365-2141.1988.tb02366.x
    1. Pacheco SE, McIntosh K, Lu M, Mofenson LM, Diaz C, Foca M, et al. Effect of perinatal antiretroviral drug exposure on hematologic values in HIV-uninfected children: an analysis of the women and infants transmission study. J Infect Dis (2006) 194(8):1089–97.10.1086/507645
    1. Ackerman WIV, Kwiek JJ. Role of the placenta in adverse perinatal outcomes among HIV-1 seropositive women. J Nippon Med Sch (2013) 80(2):90–4.10.1272/jnms.80.90
    1. Sewankambo N, Gray RH, Wawer MJ, Paxton L, McNairn D, Wabwire-Mangen F, et al. HIV-1 infection associated with abnormal vaginal flora morphology and bacterial vaginosis. Lancet (1997) 350(9077):546–50.10.1016/S0140-6736(97)01063-5
    1. Nielsen SD, Jeppesen DL, Kolte L, Clark DR, Sørensen TU, Dreves AM, et al. Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts. Blood (2001) 98(2):398–404.10.1182/blood.V98.2.398
    1. Bunders M, Thorne C, Newell ML, European Collaborative Study Maternal and infant factors and lymphocyte, CD4 and CD8 cell counts in uninfected children of HIV-1-infected mothers. AIDS (2005) 19(10):1071–9.10.1097/01.aids.0000174454.63250.22
    1. Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, Blanche S, Enquête Périnatale Française Study Group Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants. AIDS (2003) 17(14):2053–61.10.1097/00002030-200309260-00006
    1. Clerici M, Saresella M, Colombo F, Fossati S, Sala N, Bricalli D, et al. T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV. Blood (2000) 96(12):3866–71.
    1. Kakkar F, Lamarre V, Ducruet T, Boucher M, Valois S, Soudeyns H, et al. Impact of maternal HIV-1 viremia on lymphocyte subsets among HIV-exposed uninfected infants: protective mechanism or immunodeficiency. BMC Infect Dis (2014) 14:236.10.1186/1471-2334-14-236
    1. Miles DJC, Gadama L, Gumbi A, Nyalo F, Makanani B, Heyderman RS. Human immunodeficiency virus (HIV) infection during pregnancy induces CD4 T cell differentiation and modulates responses to Bacille Calmette-Guérin (BCG) vaccine in HIV-uninfected infants. Immunology (2010) 129(3):446–54.10.1111/j.1365-2567.2009.03186.x
    1. Miyamoto M, Pessoa SD, Ono E, Machado DM, Salomao R, Succi RC, et al. Low CD4+ T cell levels and B-cell apoptosis in vertically HIV exposed noninfected children and adolescents. J Trop Pediatr (2010) 56(6):427–32.10.1093/tropej/fmq024
    1. Rich K, Siegel JN, Jennings C, Rydman RJ, Landay AL. Function and phenotype of immature CD4+ lymphocytes in healthy infants and early lymphocyte activation in uninfected infants of human immunodeficiency virus-infected mothers. Clin Diagn Lab Immunol (1997) 4(3):358–61.
    1. Clerici M, Sison AV, Berzofsky JA, Rakusan TA, Brandt CD, Ellaurie M. Cellular immune factors associated with mother-to-infant transmission of HIV. AIDS (1993) 7(11):1427–33.10.1097/00002030-199311000-00004
    1. Kuhn L, Coutsoudis A, Moodley D, Trabattoni D, Mngqundaniso N, Shearer GM, et al. T-helper cell responses to HIV envelope peptides in cord blood: protection against intrapartum and breastfeeding transmission. AIDS (2001) 15(1):1–9.10.1097/00002030-200101050-00003
    1. Hygino J, Lima PG, Filho RG, Silva AA, Saramago CS, Andrade RM, et al. Altered immunological reactivity in HIV-1-exposed uninfected neonates. Clin Immunol (2008) 127(3):340–7.10.1016/j.clim.2008.01.020
    1. Chougnet C, Kovacs A, Baker R, Mueller BU, Luban NL, Liewehr DJ, et al. Influence of human immunodeficiency virus-infected maternal environment on development of infant interleukin-12 production. J Infect Dis (2000) 181(5):1590–7.10.1086/315458
    1. Mazzola TN, da Silva MTN, Abramczuk BM, Moreno YMF, Lima SCBS, Zorzeto TQ, et al. Impaired Bacillus Calmette-Guérin cellular immune response in HIV-exposed, uninfected infants. AIDS (2011) 25(17):2079–87.10.1097/QAD.0b013e32834bba0a
    1. Kidzeru EB, Hesseling AC, Passmore JAS, Myer L, Gamieldien H, Tchakoute CT, et al. In-utero exposure to maternal HIV infection alters T cell immune responses to vaccination in HIV-uninfected infants. AIDS (2014) 28(10):1421–30.10.1097/QAD.0000000000000292
    1. Cheynier R, Langlade-Demoyen P, Marescot MR, Blanche S, Blondin G, Wain-Hobson S, et al. Cytotoxic T lymphocyte responses in the peripheral blood of children born to human immunodeficiency virus-1-infected mothers. Eur J Immunol (1992) 22(9):2211–7.10.1002/eji.1830220905
    1. Rowland-Jones SL, Nixon DF, Aldhous MC, Gotch F, Ariyoshi K, Hallam N, et al. HIV-specific cyotoxic T-cell activity in an HIV-exposed but uninfected infant. Lancet (1993) 341(8849):860–1.10.1016/0140-6736(93)93063-7
    1. Aldhous MC, Watret KC, Mok JY, Bird AG, Froebel KS. Cytotoxic T lymphocyte activity and CD8 subpopulations in children at risk of HIV infection. Clin Exp Immunol (1994) 97(1):61–7.10.1111/j.1365-2249.1994.tb06580.x
    1. De Maria A, Cirillo C, Moretta L. Occurrence of human immunodeficiency virus type 1 (HIV-1)-specific cytolytic T cell activity in apparently uninfected children born to HIV-1-infected mothers. J Infect Dis (1994) 170(5):1296–9.10.1093/infdis/170.5.1296
    1. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol (2012) 12(3):180–90.10.1038/nri3156
    1. Bunders MJ, van Hamme JL, Jansen MH, Boer K, Kootstra NA, Kuijpers TW. Fetal exposure to HIV-1 alters chemokine receptor expression by CD4+T cells and increases susceptibility to HIV-1. Sci Rep (2014) 4:6690.10.1038/srep06690
    1. Kuhn L, Coutsoudis A, Moodley D, Mngqundaniso N, Trabattoni D, Shearer GM, et al. Interferon-gamma and interleukin-10 production among HIV-1-infected and uninfected infants of HIV-1-infected mothers. Pediatr Res (2001) 50(3):412–6.10.1203/00006450-200109000-00018
    1. Jardetzky TS, Brown JH, Gorga JC, Stern LJ, Urban RG, Chi YI, et al. Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen. Nature (1994) 368(6473):711–8.10.1038/368711a0
    1. Hayball JD, Robinson JH, O’Hehir RE, Verhoef A, Lamb JR, Lake RA. Identification of two binding sites in staphylococcal enterotoxin B that confer specificity for TCR V beta gene products. Int Immunol (1994) 6(2):199–211.10.1093/intimm/6.2.199
    1. Hsu PN, Huber BT. Superantigens. Gazing into the crystal ball. Curr Biol (1995) 5(3):235–7.10.1016/S0960-9822(95)00047-9
    1. Krakauer T. Update on staphylococcal superantigen-induced signaling pathways and therapeutic interventions. Toxins (Basel) (2013) 5(9):1629–54.10.3390/toxins5091629
    1. Kanellopoulos JM, De Petris S, Leca G, Crumpton MJ. The mitogenic lectin from Phaseolus vulgaris does not recognize the T3 antigen of human T lymphocytes. Eur J Immunol (1985) 15(5):479–86.10.1002/eji.1830150512
    1. Schneider OD, Millen SH, Weiss AA, Miller WE. Mechanistic insight into pertussis toxin and lectin signaling using T cells engineered to express a CD8α/CD3ζ chimeric receptor. Biochemistry (2012) 51(20):4126–37.10.1021/bi3002693
    1. Valentine MA, Tsoukas CD, Rhodes G, Vaughan JH, Carson DA. Phytohemagglutinin binds to the 20-kDa molecule of the T3 complex. Eur J Immunol (1985) 15(8):851–4.10.1002/eji.1830150821
    1. Linsley PS, Ledbetter JA. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol (1993) 11:191–212.10.1146/annurev.iy.11.040193.001203
    1. Mwanyumba F, Gaillard P, Inion I, Verhofstede C, Claeys P, Chohan V, et al. Placental inflammation and perinatal transmission of HIV-1. J Acquir Immune Defic Syndr (2002) 29(3):262–9.10.1097/00042560-200203010-00006
    1. 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:e102.10.1371/journal.pone.0000102
    1. Abu-Raya B, Smolen KK, Willems F, Kollmann TR, Marchant A. Transfer of maternal antimicrobial immunity to HIV-exposed uninfected newborns. Front Immunol (2016) 7:338.10.3389/fimmu.2016.00338
    1. Reikie BA, Naidoo S, Ruck CE, Slogrove AL, de Beer C, la Grange H, et al. Antibody responses to vaccination among South African HIV-exposed and unexposed uninfected infants during the first 2 years of life. Clin Vaccine Immunol (2013) 20(1):33–8.10.1128/CVI.00557-12
    1. Simani OE, Izu A, Violari A, Cotton MF, van Niekerk N, Adrian PV, et al. Effect of HIV-1 exposure and antiretroviral treatment strategies in HIV-infected children on immunogenicity of vaccines during infancy. AIDS (2014) 28(4):531–41.10.1097/QAD.0000000000000127
    1. Abramczuk BM, Mazzola TN, Moreno YM, Zorzeto TQ, Quintilio W, Wolf PS, et al. Impaired humoral response to vaccines among HIV-exposed uninfected infants. Clin Vaccine Immunol (2011) 18(9):1406–9.10.1128/CVI.05065-11
    1. Rutstein RM, Rudy B, Codispoti C, Watson B. Response to hepatitis B immunization by infants exposed to HIV. AIDS (1994) 8(9):1281–4.10.1097/00002030-199409000-00010
    1. Singh DK, Kumar R, Rai R, Maurya M, Bhargava A. Immunogenicity of hepatitis B vaccine in HIV exposed uninfected infants. Indian J Pediatr (2016) 83(2):172–4.10.1007/s12098-015-1905-1
    1. Jones CE, Naidoo S, De Beer C, Esser M, Kampmann B, Hesseling AC. Maternal HIV infection and antibody responses against vaccine-preventable diseases in uninfected infants. JAMA (2011) 305(6):576–84.10.1001/jama.2011.100
    1. Madhi SA, Izu A, Violari A, Cotton MF, Panchia R, Dobbels E, et al. Immunogenicity following the first and second doses of 7-valent pneumococcal conjugate vaccine in HIV-infected and -uninfected infants. Vaccine (2013) 31(5):777–83.10.1016/j.vaccine.2012.11.076
    1. Gaensbauer JT, Rakhola JT, Onyango-Makumbi C, Mubiru M, Westcott JE, Krebs NF, et al. Impaired haemophilus influenzae type b transplacental antibody transmission and declining antibody avidity through the first year of life represent potential vulnerabilities for HIV-exposed but -uninfected infants. Clin Vaccine Immunol (2014) 21(12):1661–7.10.1128/CVI.00356-14
    1. Simani OE, Adrian PV, Violari A, Kuwanda L, Otwombe K, Nunes MC, et al. Effect of in-utero HIV exposure and antiretroviral treatment strategies on measles susceptibility and immunogenicity of measles vaccine. AIDS (2013) 27(10):1583–91.10.1097/QAD.0b013e32835fae26
    1. Siberry GK, Patel K, Bellini WJ, Karalius B, Purswani MU, Burchett SK, et al. Immunity to measles, mumps, and rubella in US children with perinatal HIV infection or perinatal HIV exposure without infection. Clin Infect Dis (2015) 61(6):988–95.10.1093/cid/civ440
    1. David MC, Ha SH, Paynter S, Lau C. A systematic review and meta-analysis of management options for adults who respond poorly to hepatitis B vaccination. Vaccine (2015) 33(48):6564–9.10.1016/j.vaccine.2015.09.051
    1. Bunders MJ, Bekker V, Scherpbier HJ, Boer K, Godfried M, Kuijpers TW. Haematological parameters of HIV-1-uninfected infants born to HIV-1-infected mothers. Acta Paediatr (2005) 94(11):1571–7.10.1080/08035250510042951
    1. European Collaborative Study. Levels and patterns of neutrophil cell counts over the first 8 years of life in children of HIV-1-infected mothers. AIDS (2004) 18(15):2009–17.10.1097/00002030-200410210-00005
    1. Reikie BA, Adams RCM, Leligdowicz A, Ho K, Naidoo S, Ruck CE, et al. Altered innate immune development in HIV-exposed uninfected infants. J Acquir Immune Defic Syndr (2014) 66(3):245–55.10.1097/QAI.0000000000000161
    1. Velilla PA, Montoya CJ, Hoyos A, Moreno ME, Chougnet C, Rugeles MT. Effect of intrauterine HIV-1 exposure on the frequency and function of uninfected newborns’ dendritic cells. Clin Immunol (2008) 126(3):243–50.10.1016/j.clim.2007.11.004
    1. Slyker JA, Lohman-Payne B, John-Stewart GC, Dong T, Mbori-Ngacha D, Tapia K, et al. The impact of HIV-1 infection and exposure on natural killer (NK) cell phenotype in Kenyan infants during the first year of life. Front Immunol (2012) 3:399.10.3389/fimmu.2012.00399
    1. Gribaldo L, Malerba I, Collotta A, Casati S, Pessina A. Inhibition of CFU-E/BFU-E by 3′-azido-3′-deoxythymidine, chlorpropamide, and protoporphirin IX zinc (II): a comparison between direct exposure of progenitor cells and long-term exposure of bone marrow cultures. Toxicol Sci (2000) 58(1):96–101.10.1093/toxsci/58.1.96
    1. Fowler DA, Xie MY, Sommadossi JP. Protection and rescue from 2′,3′-dideoxypyrimidine nucleoside analog toxicity by hemin in human bone marrow progenitor cells. Antimicrob Agents Chemother (1996) 40(1):191–5.
    1. Collin M, McGovern N, Haniffa M. Human dendritic cell subsets. Immunology (2013) 140(1):22–30.10.1111/imm.12117
    1. Netea MG. Training innate immunity: the changing concept of immunological memory in innate host defence. Eur J Clin Invest (2013) 43(8):881–4.10.1111/eci.12132

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren