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Published in: Clinical and Translational Medicine 1/2018

Open Access 01-12-2018 | Research

HIV-exposed uninfected infants: elevated cord blood Interleukin 8 (IL-8) is significantly associated with maternal HIV infection and systemic IL-8 in a Kenyan cohort

Authors: Barbara Lohman-Payne, Benjamin Gabriel, Sangshin Park, Dalton Wamalwa, Elizabeth Maleche-Obimbo, Carey Farquhar, Rose Kerubo Bosire, Grace John-Stewart

Published in: Clinical and Translational Medicine | Issue 1/2018

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Abstract

Background

In low and middle income countries, human immunodeficiency virus (HIV) exposed, uninfected (HEU) infants demonstrate higher morbidity and mortality than their unexposed counterparts. To determine possible immune correlates of this effect, we investigated the impact of in utero HIV exposure on the uninfected neonatal immune milieu and maternal factors mediating these abnormalities in a cohort of vaginally delivered mother-infants. Samples of delivery and cord blood plasma were selected from 22 Kenyan HIV-infected women and their HIV exposed uninfected (HEU) infants drawn from the pre-ARV era, while 19 Kenyan HIV-uninfected (HU) women and their infants were selected from a control cohort.

Results

Compared to HU cord plasma, HEU cord plasma contained significantly higher levels of pro-inflammatory cytokines interleukins (IL)-6 and -8 (both p < 0.001) and significantly lower levels of CXC motif chemokine 11 (CXC11) (p < 0.001). Mediation analysis demonstrated that maternal HIV infection status was a significant determinant of infant IL-8 responses: HEU status was associated with a ninefold higher infant:mother (cord:delivery) plasma levels of IL-8 (p < 0.005), whereas maternal viral load was negatively associated with HEU IL-8 levels (p = 0.04) and not associated with HEU IL-6 levels.

Conclusions

Exposure to maternal HIV infection drives an increase in prenatal IL-8 that is partially mediated by maternal cytokine levels. Differences between maternal and infant cytokine levels strongly suggest independent modulation in utero, consistent with prenatal immune activation. Elevated pro-inflammatory signals at birth may interfere with T cell responses at birth and subsequently influence immune maturation and the risk of morbidity and mortality in HEU infants.
Literature
1.
go back to reference Koyanagi A, Humphrey JH, Ntozini R, Nathoo KJ, Moulton LH, Iliff PJ et al (2011) 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 30:45–51CrossRefPubMed Koyanagi A, Humphrey JH, Ntozini R, Nathoo KJ, Moulton LH, Iliff PJ et al (2011) 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 30:45–51CrossRefPubMed
2.
go back to reference Breenan AT, Bonawitz R, Gill CJ, Thea DM, Kleinman M, Useem J et al (2016) A meta-analysis assessing all-cause mortality in HIV-exposed uninfected compared with HIV-unexposed uninfected infants and children. AIDS 30:2351–2360CrossRef Breenan AT, Bonawitz R, Gill CJ, Thea DM, Kleinman M, Useem J et al (2016) A meta-analysis assessing all-cause mortality in HIV-exposed uninfected compared with HIV-unexposed uninfected infants and children. AIDS 30:2351–2360CrossRef
3.
go back to reference Clerici M, Saresella M, Colombo F, Fossati S, Sala N, Bricalli D et al (2000) T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV. Blood 96(12):3866–3871PubMed Clerici M, Saresella M, Colombo F, Fossati S, Sala N, Bricalli D et al (2000) T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV. Blood 96(12):3866–3871PubMed
4.
go back to reference Bunders M, Thorne C, Newell ML, Study ftEC (2005) Maternal and infant factors and lymphocyte, CD4 and CD8 cell counts in uninfected children of HIV-1-infected mothers. AIDS 19:1071–1079CrossRefPubMed Bunders M, Thorne C, Newell ML, Study ftEC (2005) Maternal and infant factors and lymphocyte, CD4 and CD8 cell counts in uninfected children of HIV-1-infected mothers. AIDS 19:1071–1079CrossRefPubMed
5.
go back to reference Borges-Almeida E, Milanez HM, Vilela MMS, Cunha FGP, Abramczuk RM, Reiz-Alves SC et al (2011) The impact of maternal HIV infection on cord blood lymphocyte subsets and cytokine profile in exposed non-infected newborns. BMC Infect Dis 11:38CrossRefPubMedPubMedCentral Borges-Almeida E, Milanez HM, Vilela MMS, Cunha FGP, Abramczuk RM, Reiz-Alves SC et al (2011) The impact of maternal HIV infection on cord blood lymphocyte subsets and cytokine profile in exposed non-infected newborns. BMC Infect Dis 11:38CrossRefPubMedPubMedCentral
6.
go back to reference Legrand FA, Nixon DF, Loo CP, Ono E, Chapman JM, Miyamoto M et al (2006) Strong HIV-1-specific T cell responses in HIV-1-exposed uninfected infants and neonates revealed after regulatory T cell removal. PLoS ONE 1:e102CrossRefPubMedPubMedCentral Legrand FA, Nixon DF, Loo CP, Ono E, Chapman JM, Miyamoto M et al (2006) Strong HIV-1-specific T cell responses in HIV-1-exposed uninfected infants and neonates revealed after regulatory T cell removal. PLoS ONE 1:e102CrossRefPubMedPubMedCentral
7.
go back to reference John-Stewart GC, Mbori-Ngacha D, Lohman-Payne B, Farquhar C, Richardson BA, Emery S et al (2009) HIV-1-specific cytotoxic T lymphocytes and breast milk HIV-1 transmission. J Infect Dis 199:889–898CrossRefPubMedPubMedCentral John-Stewart GC, Mbori-Ngacha D, Lohman-Payne B, Farquhar C, Richardson BA, Emery S et al (2009) HIV-1-specific cytotoxic T lymphocytes and breast milk HIV-1 transmission. J Infect Dis 199:889–898CrossRefPubMedPubMedCentral
8.
go back to reference Kuhn L, Meddows-Taylor S, Gray G, Trabattoni D, Clerici M, Shearer GM et al (2001) Reduced HIV-stimulated T-helper cell reactivity in cord blood with short-course antiretroviral treatment for prevention of maternal-infant transmission. Clin Exp Immunol 123(3):443–450CrossRefPubMedPubMedCentral Kuhn L, Meddows-Taylor S, Gray G, Trabattoni D, Clerici M, Shearer GM et al (2001) Reduced HIV-stimulated T-helper cell reactivity in cord blood with short-course antiretroviral treatment for prevention of maternal-infant transmission. Clin Exp Immunol 123(3):443–450CrossRefPubMedPubMedCentral
9.
go back to reference Reikie BA, Adams RCM, Leligdowicz A, Ho K, Naidoo S, Ruck CE et al (2014) Altered innate immune development in HIV-exposed uninfected infants. J Acquir Immune Defic Syndr 66:245–255CrossRefPubMedPubMedCentral Reikie BA, Adams RCM, Leligdowicz A, Ho K, Naidoo S, Ruck CE et al (2014) Altered innate immune development in HIV-exposed uninfected infants. J Acquir Immune Defic Syndr 66:245–255CrossRefPubMedPubMedCentral
10.
go back to reference Nduati R, John G, Mbori-Ngacha D, Richardson B, Overbaugh J, Mwatha A et al (2000) Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 283(9):1167–1174CrossRefPubMed Nduati R, John G, Mbori-Ngacha D, Richardson B, Overbaugh J, Mwatha A et al (2000) Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 283(9):1167–1174CrossRefPubMed
11.
go back to reference Emery S, Bodrug S, Richardson BA, Giachetti C, Bott MA, Panteleeff D et al (2000) Evaluation of performance of the Gen-Probe human immunodeficiency virus type 1 viral load assay using primary subtype A, C, and D isolates from Kenya. J Clin Microbiol 38(7):2688–2695PubMedPubMedCentral Emery S, Bodrug S, Richardson BA, Giachetti C, Bott MA, Panteleeff D et al (2000) Evaluation of performance of the Gen-Probe human immunodeficiency virus type 1 viral load assay using primary subtype A, C, and D isolates from Kenya. J Clin Microbiol 38(7):2688–2695PubMedPubMedCentral
12.
go back to reference DeVange Panteleeff D, John GC, Nduati R, Mbori-Ngacha D, Richardson BA, Kreiss JK et al (1999) Rapid method for screening dried blood samples on filter paper for human immunodeficiency virus type 1 DNA. J Clin Microbiol 37:350–353 DeVange Panteleeff D, John GC, Nduati R, Mbori-Ngacha D, Richardson BA, Kreiss JK et al (1999) Rapid method for screening dried blood samples on filter paper for human immunodeficiency virus type 1 DNA. J Clin Microbiol 37:350–353
13.
go back to reference Bosire R, Guthrie BL, Lohman-Payne BL, Mabuka JM, Majiwa M, Wariua G et al (2007) Longitudinal comparison of chemokines in breastmilk early postpartum among HIV-1 infected and uninfected Kenyan women. Breastfeed Med 2:129–138CrossRefPubMedPubMedCentral Bosire R, Guthrie BL, Lohman-Payne BL, Mabuka JM, Majiwa M, Wariua G et al (2007) Longitudinal comparison of chemokines in breastmilk early postpartum among HIV-1 infected and uninfected Kenyan women. Breastfeed Med 2:129–138CrossRefPubMedPubMedCentral
14.
go back to reference Spirtes P, Zhang K (2016) Causal discovery and inference: concepts and recent methodological advances. Appl Inform 3:3CrossRef Spirtes P, Zhang K (2016) Causal discovery and inference: concepts and recent methodological advances. Appl Inform 3:3CrossRef
15.
go back to reference Marsh HW, Morin AJS, Parker PD, Kaur G (2014) Exploratory structural equation modeling: an intergration of the best features of exploratory and confirmatory factor analysis. Annu Rev Clin Pychol 10:85–110CrossRef Marsh HW, Morin AJS, Parker PD, Kaur G (2014) Exploratory structural equation modeling: an intergration of the best features of exploratory and confirmatory factor analysis. Annu Rev Clin Pychol 10:85–110CrossRef
16.
go back to reference Reisenberger K, Egarter C, Vogl C, Sternerger B, Kiss H, Husslein P (1996) The transfer of interleukin-8 across the human placenta perfused in vitro. Obstet Gynecol 87:613–616CrossRefPubMed Reisenberger K, Egarter C, Vogl C, Sternerger B, Kiss H, Husslein P (1996) The transfer of interleukin-8 across the human placenta perfused in vitro. Obstet Gynecol 87:613–616CrossRefPubMed
17.
go back to reference Cicarelli LM, Perroni AG, Zugaib M, Basto de Albuquerque P, Campa A (2005) Maternal and cord blood levels of serum amyloid A, C-reactive protein, tumor necrosis, factor-a, interleukin-1b, and interleukin-8 during and after delivery. Mediat Inflamm 2:96–100CrossRef Cicarelli LM, Perroni AG, Zugaib M, Basto de Albuquerque P, Campa A (2005) Maternal and cord blood levels of serum amyloid A, C-reactive protein, tumor necrosis, factor-a, interleukin-1b, and interleukin-8 during and after delivery. Mediat Inflamm 2:96–100CrossRef
18.
go back to reference Turner MD, Nedjai B, Hurst T, Pennington DJ (2014) Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochem Biophys Acta 1843:2563–2582CrossRefPubMed Turner MD, Nedjai B, Hurst T, Pennington DJ (2014) Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochem Biophys Acta 1843:2563–2582CrossRefPubMed
19.
go back to reference Bowen J, Chamley L, Keelan JA, Mitchell MD (2002) Cytokines of the placenta and extra-placental membranes: roles and regulation druing human pregnancy and partuition. Placenta 23:257–273CrossRefPubMed Bowen J, Chamley L, Keelan JA, Mitchell MD (2002) Cytokines of the placenta and extra-placental membranes: roles and regulation druing human pregnancy and partuition. Placenta 23:257–273CrossRefPubMed
20.
go back to reference Tornblom SA, Klimaviciute A, Bystrom B, Chromek M, Brauner A, Ekman-Ordeberg E (2005) Non-infected preterm parturition is related to increased concentrations of IL-6, IL-8 and MCP-1 in human cervix. Reprod Biol Endrocrinol 3:39CrossRef Tornblom SA, Klimaviciute A, Bystrom B, Chromek M, Brauner A, Ekman-Ordeberg E (2005) Non-infected preterm parturition is related to increased concentrations of IL-6, IL-8 and MCP-1 in human cervix. Reprod Biol Endrocrinol 3:39CrossRef
21.
go back to reference Boles JL, Ross MG, Beloosesky R, Sesai M, Belkacemi L (2012) Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus. J Inflamm Res 5:67–75PubMedPubMedCentral Boles JL, Ross MG, Beloosesky R, Sesai M, Belkacemi L (2012) Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus. J Inflamm Res 5:67–75PubMedPubMedCentral
22.
go back to reference Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S et al (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12:1365–1371CrossRefPubMed Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S et al (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12:1365–1371CrossRefPubMed
23.
go back to reference Koga K, Izumi G, Mor G, Fujii T, Osuga Y (2014) Toll-like receptors at teh maternal-fetal interface in normal pregnancy and pregnancy complications. Am J Reprod Immunol 72:192–205CrossRefPubMed Koga K, Izumi G, Mor G, Fujii T, Osuga Y (2014) Toll-like receptors at teh maternal-fetal interface in normal pregnancy and pregnancy complications. Am J Reprod Immunol 72:192–205CrossRefPubMed
24.
go back to reference Gasparoni A, Ciardelli L, Avanzini A, Castellazzi AM, Carini R, Rondini G et al (2003) Age-related changes in intracellular TH1/TH2 cytokine production, immunoproliferative T lymphocyte response and natural killer cell activity in newborns, children, and adults. Biol Neonate 84(4):297–303CrossRefPubMed Gasparoni A, Ciardelli L, Avanzini A, Castellazzi AM, Carini R, Rondini G et al (2003) Age-related changes in intracellular TH1/TH2 cytokine production, immunoproliferative T lymphocyte response and natural killer cell activity in newborns, children, and adults. Biol Neonate 84(4):297–303CrossRefPubMed
25.
go back to reference Kotiranta-Ainamo A, Rautonen J, Rautonen N (2004) Imbalanced cytokine secretion in newborns. Biol Neonate 85:55–60CrossRefPubMed Kotiranta-Ainamo A, Rautonen J, Rautonen N (2004) Imbalanced cytokine secretion in newborns. Biol Neonate 85:55–60CrossRefPubMed
26.
go back to reference Ott M, Lovett JL, Mueller L, Verdin E (1998) Superinduction of IL-8 in T cells by HIV-1 tat protein is mediated through NF-kappaB factors. J Immunol 160(6):2872–2880PubMed Ott M, Lovett JL, Mueller L, Verdin E (1998) Superinduction of IL-8 in T cells by HIV-1 tat protein is mediated through NF-kappaB factors. J Immunol 160(6):2872–2880PubMed
27.
go back to reference Mahieux R, Lambert PF, Agbottah E, Halanski MA, Deng L, Kashanchi F et al (2001) Cell cycle regulation of human interleukin-8 gene expression by the human immunodeficiency virus type 1 tat protein. J Virol 75(4):1736–1743CrossRefPubMedPubMedCentral Mahieux R, Lambert PF, Agbottah E, Halanski MA, Deng L, Kashanchi F et al (2001) Cell cycle regulation of human interleukin-8 gene expression by the human immunodeficiency virus type 1 tat protein. J Virol 75(4):1736–1743CrossRefPubMedPubMedCentral
28.
go back to reference Miyamoto M, Gouvea A, Ono E, Succi R, Pahwa S, Moraes-Pinto M (2017) Immune development in HIV-exposed uninfected children born to HIV-infected women. Rev Inst Med Trop Sao Paulo 59:e30CrossRefPubMedPubMedCentral Miyamoto M, Gouvea A, Ono E, Succi R, Pahwa S, Moraes-Pinto M (2017) Immune development in HIV-exposed uninfected children born to HIV-infected women. Rev Inst Med Trop Sao Paulo 59:e30CrossRefPubMedPubMedCentral
Metadata
Title
HIV-exposed uninfected infants: elevated cord blood Interleukin 8 (IL-8) is significantly associated with maternal HIV infection and systemic IL-8 in a Kenyan cohort
Authors
Barbara Lohman-Payne
Benjamin Gabriel
Sangshin Park
Dalton Wamalwa
Elizabeth Maleche-Obimbo
Carey Farquhar
Rose Kerubo Bosire
Grace John-Stewart
Publication date
01-12-2018
Publisher
Springer Berlin Heidelberg
Published in
Clinical and Translational Medicine / Issue 1/2018
Electronic ISSN: 2001-1326
DOI
https://doi.org/10.1186/s40169-018-0206-5

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