HIV-exposed-uninfected infants have increased inflammation and monocyte activation

Dirajlal-Fargo, Sahera; Mussi-Pinhata, Marisa Márcia; Weinberg, Adriana; Yu, Qilu; Cohen, Rachel; Harris, D.R.; Bowman, Emily; Gabriel, Janelle; Kulkarni, Milind V.; Funderburg, Nicholas T.; Chakhtoura, Nahida; McComsey, Grace A.; Protocol, Nisdi Lilac

doi:10.1097/qad.0000000000002128

Cited by 53 publications

(41 citation statements)

References 46 publications

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“…Pro- and anti-inflammatory cytokines have been used as an indicator of immune regulation in the majority of existing studies with HEU children ( Borges-Almeida et al, 2011 , Chougnet et al, 2000 , Dirajlal-Fargo et al, 2019 , Miyamoto et al, 2017 , Prendergast et al, 2017 ), pregnant women living with HIV ( Faye et al, 2007 , Maharaj et al, 2017 , Moussa et al, 2001 , Richardson and Weinberg, 2011 , Sachdeva et al, 2008 ) and brain disorders in children ( Miyamoto et al, 2017 ). Serum neutrophil gelatinase-associated lipocalin (NGAL) levels were shown to be associated with cognitive impairments and reduced brain volumes in people living with HIV ( Williams et al, 2019 , Williams et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

“…The vulnerability of the immune system in HEU children is also suggested by the increase in morbidity and mortality in HEU infants ( Afran et al, 2014 ). However, results on HEU children inflammatory profiles are inconsistent, with evidence for both increased levels ( Dirajlal-Fargo et al, 2019 , Miyamoto et al, 2017 , Prendergast et al, 2017 ) as well as reduced levels of cytokines in HEU children ( Borges-Almeida et al, 2011 , Chougnet et al, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

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Association of maternal and infant inflammation with neurodevelopment in HIV-exposed uninfected children in a South African birth cohort

Sevenoaks

Wedderburn

Donald

et al. 2021

Brain, Behavior, and Immunity

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of maternal and infant inflammation with neurodevelopment in HIV-exposed uninfected children in a South African birth cohort

Sevenoaks

Wedderburn

Donald

et al. 2021

Brain, Behavior, and Immunity

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“…Since ERAP2 shows a strong preference for basic arginine residue trimming (2) and supplies of free-Arg are essential for maximum NO synthesis (21), it is tempting to speculate that stressor-induced ERAP2 secretion could have direct and indirect effects on macrophage activation, or more broadly on pro-inflammatory response. This, in turn, could constitute a favorable environment, raising an immune barrier that could interfere with HIV entry, as suggested by several studies portraying the profile of subjects who naturally resist HIV-1 infection (40–46).…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Associated Aminopeptidase 2 (ERAP2) Is Released in the Secretome of Activated MDMs and Reduces in vitro HIV-1 Infection

et al. 2019

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Background: Haplotype-specific alternative splicing of the endoplasmic reticulum (ER) aminopeptidase type 2 (ERAP2) gene results in either full-length (FL, haplotype A) or alternatively spliced (AS, haplotype B) mRNA. HapA/HapA homozygous (HomoA) subjects show a reduced susceptibility to HIV-1 infection, probably secondary to the modulation of the antigen processing/presenting machinery. ERAP1 was recently shown to be secreted from the plasma membrane in response to activation; we investigated whether ERAP2 can be released as well and if the secreted form of this enzyme retains its antiviral function. Methods: Human monocyte derived macrophages (MDMs) were differentiated from peripheral blood mononuclear cells (PBMCs) isolated from 6 HomoA healthy controls and stimulated with IFNγ and LPS. ERAP2-FL secretion was evaluated by mass spectrometry. PBMCs (14 HomoA and 16 HomoB) and CD8-depleted PBMCs (CD8 − PBMCs) (4 HomoA and 4 HomoB) were in vitro HIV-infected in the absence/presence of recombinant human ERAP2-FL (rhERAP2) protein; p24 viral antigen quantification was used to assess viral replication. IFNγ and CD69 mRNA expression, as well as the percentage of perforin-producing CD8+ T Lymphocytes, were analyzed 3 and 7-days post in vitro HIV-1-infection, respectively. The effect of rhERAP2 addition in cell cultures on T cell apoptosis, proliferation, activation, and maturation was evaluated as well on 24 h-stimulated PBMCs. Results: ERAP2 can be secreted from human MDMs in response to IFNγ/LPS stimulation. Notably, the addition of rhERAP2 to PBMC and CD8 − PBMC cultures resulted in the reduction of viral replication, though these differences were statistically significant only in PBMCs ( p < 0.05 in both HomoA and HomoB). This protective effect was associated with an increase in IFNγ and CD69 mRNA expression and in the percentage of perforin-expressing CD107 + CD8 + cells. RhERAP2 addition also resulted in an increase in CD8 + activated lymphocyte (CD25 + HLA − DRII + ) and Effector Memory/Terminally differentiated CD8 + T cells ratio. Conclusions: This is the first report providing evidence for the release of ERAP2 in the secretome of immunocompetent cells. Data herein also indicate that exogenous ERAP2-FL exerts its protective function against HIV-1 infection, even in HomoB subjects who do not genetically produce it. Presumably, this defensive extracellular feature is only partially dependent on immune system modulation.

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“…HEU infants show aberrations of the immune system at birth [ 55 – 57 ] with systemic immune activation [ 56 , 58 ] which could be linked to adverse health outcomes [ 59 , 60 ]. HEU infants also have lower antibody titres following vaccination [ 61 , 62 ] with abnormal B- and T-lymphocyte phenotypic profiles [ 63 , 64 ].…”

Section: Introductionmentioning

confidence: 99%

The University of Zimbabwe College of Health Sciences (UZ-CHS) BIRTH COHORT study: rationale, design and methods

Duri

Gumbo²,

Munjoma

et al. 2020

BMC Infect Dis

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Background Commencing lifelong antiretroviral therapy (ART) immediately following HIV diagnosis (Option B+), has greatly improved maternal-infant health. Thus, large and increasing numbers of HIV-infected women are on ART during pregnancy, a situation concurrently increasing numbers of HIV-exposed-uninfected (HEU) infants. Compared to their HIV-unexposed-uninfected (HUU) counterparts, HEU infants show higher rates of adverse birth outcomes, mortality, infectious/non-communicable diseases including impaired growth and neurocognitive development. There is an urgent need to understand the impact of HIV and early life ART exposures, immune-metabolic dysregulation, comorbidities and environmental confounders on adverse paediatric outcomes. Methods Six hundred (600) HIV-infected and 600 HIV-uninfected pregnant women ≥20 weeks of gestation will be enrolled from four primary health centres in high density residential areas of Harare. Participants will be followed up as mother-infant-pairs at delivery, week(s) 1, 6, 10, 14, 24, 36, 48, 72 and 96 after birth. Clinical, socio-economic, nutritional and environmental data will be assessed for adverse birth outcomes, impaired growth, immune/neurodevelopment, vertical transmission of HIV, hepatitis-B/C viruses, cytomegalovirus and syphilis. Maternal urine, stool, plasma, cord blood, amniotic fluid, placenta and milk including infant plasma, dried blood spot and stool will be collected at enrolment and follow-up visits. The composite primary endpoint is stillbirth and infant mortality within the first two years of life in HEU versus HUU infants. Maternal mortality in HIV-infected versus -uninfected women is another primary outcome. Secondary endpoints include a range of maternal and infant outcomes. Sub-studies will address maternal stress and malnutrition, maternal-infant latent tuberculosis, Helicobacter pylori infections, immune-metabolomic dysregulation including gut, breast milk and amniotic fluid dysbiosis. Discussion The University of Zimbabwe-College of Health-Sciences-Birth-Cohort study will provide a comprehensive assessment of risk factors and biomarkers for HEU infants’ adverse outcomes. This will ultimately help developing strategies to mitigate effects of maternal HIV, early-life ART exposures and comorbidities on infants’ mortality and morbidity. Trial registration ClinicalTrial.gov Identifier: NCT04087239. Registered 12 September 2019.

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HIV-exposed-uninfected infants have increased inflammation and monocyte activation

Cited by 53 publications

References 46 publications

Association of maternal and infant inflammation with neurodevelopment in HIV-exposed uninfected children in a South African birth cohort

Association of maternal and infant inflammation with neurodevelopment in HIV-exposed uninfected children in a South African birth cohort

Endoplasmic Reticulum Associated Aminopeptidase 2 (ERAP2) Is Released in the Secretome of Activated MDMs and Reduces in vitro HIV-1 Infection

The University of Zimbabwe College of Health Sciences (UZ-CHS) BIRTH COHORT study: rationale, design and methods

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