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  • 1
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    Online Resource
    Circulating angiogenic factors and HIV among pregnant women in Zambia: a nested case–control study
    Springer Science and Business Media LLC ; 2021
    In:  BMC Pregnancy and Childbirth Vol. 21, No. 1 ( 2021-12)
    Details
    In: BMC Pregnancy and Childbirth, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2021-12)
    Abstract: Maternal HIV increases the risk of adverse birth outcomes including preterm birth, fetal growth restriction, and stillbirth, but the biological mechanism(s) underlying this increased risk are not well understood. We hypothesized that maternal HIV may lead to adverse birth outcomes through an imbalance in angiogenic factors involved in the vascular endothelial growth factor (VEGF) signaling pathway. Methods In a case–control study nested within an ongoing cohort in Zambia, our primary outcomes were serum concentrations of VEGF-A, soluble endoglin (sEng), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFLT-1). These were measured in 57 women with HIV (cases) and 57 women without HIV (controls) before 16 gestational weeks. We used the Wilcoxon rank-sum and linear regression controlling for maternal body mass index (BMI) and parity to assess the difference in biomarker concentrations between cases and controls. We also used logistic regression to test for associations between biomarker concentration and adverse pregnancy outcomes (preeclampsia, preterm birth, small for gestational age, stillbirth, and a composite of preterm birth or stillbirth). Results Compared to controls, women with HIV had significantly lower median concentrations of PlGF (7.6 vs 10.2 pg/mL, p  = 0.02) and sFLT-1 (1647.9 vs 2055.6 pg/mL, p  = 0.04), but these findings were not confirmed in adjusted analysis. PlGF concentration was lower among women who delivered preterm compared to those who delivered at term (6.7 vs 9.6 pg/mL, p  = 0.03) and among those who experienced the composite adverse birth outcome (6.2 vs 9.8 pg/mL, p  = 0.02). Median sFLT-1 concentration was lower among participants with the composite outcome (1621.0 vs 1945.9 pg/mL, p  = 0.04), but the association was not significant in adjusted analysis. sEng was not associated with either adverse birth outcomes or HIV. VEGF-A was undetectable by Luminex in all specimens. Conclusions We present preliminary findings that HIV is associated with a shift in the VEGF signaling pathway in early pregnancy, although adjusted analyses were inconclusive. We confirm an association between angiogenic biomarkers and adverse birth outcomes in our population. Larger studies are needed to further elucidate the role of HIV on placental angiogenesis and adverse birth outcomes.
    Type of Medium: Online Resource
    ISSN: 1471-2393
    URL: Article
    DOI: 10.1186/s12884-021-03965-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2059869-5
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  • 2
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    Simian-Human Immunodeficiency Virus SHIV.CH505-Infected Infant and Adult Rhesus Macaques Exhibit Similar Env-Specific Antibody Kinetics, despite Distinct T-Follicular Helper and Germinal Center B Cell Landscapes
    American Society for Microbiology ; 2019
    In:  Journal of Virology Vol. 93, No. 15 ( 2019-08)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 93, No. 15 ( 2019-08)
    Abstract: Global elimination of pediatric human immunodeficiency virus (HIV) infections will require the development of novel immune-based approaches, and understanding infant immunity to HIV is critical to guide the rational design of these intervention strategies. Despite their immunological immaturity, chronically HIV-infected children develop broadly neutralizing antibodies (bnAbs) more frequently and earlier than adults do. However, the ontogeny of humoral responses during acute HIV infection is poorly defined in infants and challenging to study in human cohorts due to the presence of maternal antibodies. To further our understanding of age-related differences in the development of HIV-specific immunity during acute infection, we evaluated the generation of virus-specific humoral immune responses in infant ( n  = 6) and adult ( n  = 12) rhesus macaques (RMs) infected with a transmitted/founder (T/F) simian-human immunodeficiency virus (SHIV) (SHIV.C.CH505 [CH505]). The plasma HIV envelope-specific IgG antibody kinetics were similar in SHIV-infected infant and adult RMs, with no significant differences in the magnitude or breadth of these responses. Interestingly, autologous tier 2 virus neutralization responses also developed with similar frequencies and kinetics in infant and adult RMs, despite infants exhibiting significantly higher follicular T helper cell (Tfh) and germinal center B cell frequencies than adults. Finally, we show that plasma viral load was the strongest predictor of the development of autologous virus neutralization in both age groups. Our results indicate that the humoral immune response to SHIV infection develops with similar kinetics among infant and adult RMs, suggesting that the early-life immune system is equipped to respond to HIV-1 and promote the production of neutralizing HIV antibodies. IMPORTANCE There is a lack of understanding of how the maturation of the infant immune system influences immunity to HIV infection or how these responses differ from those of adults. Improving our knowledge of infant HIV immunity will help guide antiviral intervention strategies that take advantage of the unique infant immune environment to successfully elicit protective immune responses. We utilized a rhesus macaque model of SHIV infection as a tool to distinguish the differences in HIV humoral immunity in infants versus adults. Here, we demonstrate that the kinetics and quality of the infant humoral immune response to HIV are highly comparable to those of adults during the early phase of infection, despite distinct differences in their Tfh responses, indicating that slightly different mechanisms may drive infant and adult humoral immunity.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.00168-19
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
    detail.hit.zdb_id: 1495529-5
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  • 3
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    Intracellular Tenofovir and Emtricitabine Concentrations in Younger and Older Women with HIV Receiving Tenofovir Disoproxil Fumarate/Emtricitabine
    American Society for Microbiology ; 2020
    In:  Antimicrobial Agents and Chemotherapy Vol. 64, No. 9 ( 2020-08-20)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 64, No. 9 ( 2020-08-20)
    Abstract: The altered immune states of aging and HIV infection may affect intracellular metabolism of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC); increased cellular senescence decreases FTC-triphosphate (FTCtp) concentrations. The effects of age and inflammation on the ratio of intracellular metabolites (IMs; tenofovir diphosphate [TFVdp] and FTCtp) to their endogenous nucleotides (ENs; dATP and dCTP), a potential treatment efficacy marker, were assessed among participants of the Women’s Interagency HIV Study (WIHS), who ranged from 25 to 75 years. Samples from women receiving TDF-FTC with viral loads of 〈 200 copies/ml were dichotomized by age at collection into two groups (≤45 years and ≥60 years). IM/EN concentrations were measured in peripheral blood mononuclear cell (PBMC) pellets; interleukin-6 (IL-6) and sCD163 were measured in plasma; senescent CD8 + T cells were measured in viable PBMCs. The TFVdp:dATP and FTCtp:dCTP ratios had statistically significantly different distributions in older and younger women (log-rank test, P  = 0.0023 and P  = 0.032, respectively); in general, IM and EN concentrations were higher in the older women. After adjusting for potential confounders, these findings were not significant. In women aged ≤45 years, TFVdp was negatively associated with IL-6 and sCD163, while FTCtp was positively associated with sCD163 and IL-6 in women aged ≥60 years. Body mass index (BMI) was positively associated with IL-6 in both age groups and negatively associated with TFVdp in women aged ≤45 years. After adjustment, age remained significant for sCD163, while black race, BMI, and renal function remained significant for several IMs and ENs, suggesting that factors associated with aging, but not age itself, govern intracellular TDF-FTC pharmacology.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00177-20
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 4
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    Coadministration of CH31 Broadly Neutralizing Antibody Does Not Affect Development of Vaccine-Induced Anti-HIV-1 Envelope Antibody Responses in Infant Rhesus Macaques
    American Society for Microbiology ; 2019
    In:  Journal of Virology Vol. 93, No. 5 ( 2019-03)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 93, No. 5 ( 2019-03)
    Abstract: Prevention of mother-to-child transmission (MTCT) is an indispensable component in combatting the global AIDS epidemic. A combination of passive broadly neutralizing antibody (bnAb) infusion and active vaccination promises to provide protection of infants against MTCT from birth through the breastfeeding period and could prime the immune system for lifelong immunity. In this study, we investigate the impact of a single infusion of CD4 binding site (CD4bs) bnAb administered at birth on de novo antibody responses elicited by concurrent active HIV envelope vaccination. Four groups of infant macaques received active immunizations with subunit Env protein or modified vaccinia Ankara (MVA)-vectored Env and subunit Env protein, with or without a single intravenous coadministration of CH31 bnAb at birth. Vaccinated animals were monitored to evaluate binding and functional antibody responses elicited by the active vaccinations. Despite achieving plasma concentrations that were able to neutralize tier 2 viruses, coadministration of CH31 did not have a large impact on the kinetics, magnitude, specificity, or avidity of vaccine-elicited binding or functional antibody responses, including epitope specificity, the development of CD4bs antibodies, neutralization, binding to infected cells, or antibody-dependent cell-mediated cytotoxicity (ADCC). We conclude that infusion of CD4bs bnAb CH31 at birth does not interfere with de novo antibody responses to active vaccination and that a combination of passive bnAb infusion and active HIV-1 Env vaccination is a viable strategy for immediate and prolonged protection against MTCT. IMPORTANCE Our study is the first to evaluate the impact of passive infusion of a broadly neutralizing antibody in newborns on the de novo development of antibody responses following active vaccinations in infancy. We demonstrated the safety and the feasibility of bnAb administration to achieve biologically relevant levels of the antibody and showed that the passive infusion did not impair the de novo antibody production following HIV-1 Env vaccination. Our study paves the way for further investigations of the combination strategy using passive plus active immunization to provide protection of infants born to HIV-1-positive mothers over the entire period of risk for mother-to-child transmission.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01783-18
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
    detail.hit.zdb_id: 1495529-5
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  • 5
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    Adjuvant-Dependent Enhancement of HIV Env-Specific Antibody Responses in Infant Rhesus Macaques
    American Society for Microbiology ; 2018
    In:  Journal of Virology Vol. 92, No. 20 ( 2018-10-15)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 92, No. 20 ( 2018-10-15)
    Abstract: Toward the goal of developing an effective HIV vaccine that can be administered in infancy to protect against postnatal and lifelong sexual HIV transmission risks, the current pilot study was designed to compare the effect of novel adjuvants on the induction of HIV Env-specific antibody responses in infant macaques. Aligning our studies with the adjuvanted proteins evaluated in a prime-boost schedule with ALVAC in the ongoing HVTN (HIV Vaccine Trials Network) 702 efficacy trial, we selected the bivalent clade C Env immunogens gp120 C.1086 and gp120 TV1 in combination with the MF59 adjuvant. However, we hypothesized that the adjuvant system AS01, that is included in the pediatric RTS,S malaria vaccine, would promote Env-specific antibody responses superior to those of the oil-in-water MF59 emulsion adjuvant. In a second study arm, we compared two emulsions, glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) and 3M-052-SE, containing Toll-like receptor 4 (TLR4) and TLR7/TLR8 (TLR7/8) ligand, respectively. The latter adjuvant had been previously demonstrated to be especially effective in activating neonatal antigen-presenting cells. Our results demonstrate that different adjuvants drive quantitatively or qualitatively distinct responses to the bivalent Env vaccine. AS01 induced higher Env-specific plasma IgG antibody levels than the antigen in MF59 and promoted improved antibody function in infants, and 3M-052-SE outperformed GLA-SE by inducing the highest breadth and functionality of antibody responses. Thus, distinct adjuvants are likely to be required for maximizing vaccine-elicited immune responses in infants, particularly when immunization in infancy aims to elicit both perinatal and lifelong immunity against challenging pathogens such as HIV. IMPORTANCE Alum remains the adjuvant of choice for pediatric vaccines. Yet the distinct nature of the developing immune system in infants likely requires novel adjuvants targeted specifically at the pediatric population to reach maximal vaccine efficacy with an acceptable safety profile. The current study supports the idea that additional adjuvants for pediatric vaccines should be, and need to be, tested in infants for their potential to enhance immune responses. Using an infant macaque model, our results suggest that both AS01 and 3M-052-SE can significantly improve and better sustain HIV Env-specific antibody responses than alum. Despite the limited number of animals, the results revealed interesting differences that warrant further testing of promising novel adjuvant candidates in larger preclinical and clinical studies to define the mechanisms leading to adjuvant-improved antibody responses and to identify targets for adjuvant and vaccine optimization.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01051-18
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2018
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  • 6
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    Online Resource
    The effect of age on CD4+ T-cell recovery in HIV-suppressed adult participants: a sub-study from AIDS Clinical Trial Group (ACTG) A5321 and the Bone Loss and Immune Reconstitution (BLIR) study
    Springer Science and Business Media LLC ; 2022
    In:  Immunity & Ageing Vol. 19, No. 1 ( 2022-12)
    Details
    In: Immunity & Ageing, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2022-12)
    Abstract: Older age could be a risk factor for suboptimal CD4+ T-cell recovery in HIV-infected patients despite successful viral suppression. However, evaluation of this effect could be confounded by age-related immune processes such as decreased thymus output, increased immune activation and exhaustion. Here, we established a semi-mechanistic population model simultaneously describing naïve and memory CD4+ T-cell trajectories in 122 participants. Covariate analysis accounting for immune activation showed that older age was significantly associated with faster apparent elimination rate of the naïve T-cells. In addition, female sex predicted slower apparent elimination rate of memory T-cells. Simulations showed that the median maximal CD4+ T-cell count on ART treatment was 593 cells/μL (IQR 442-794) in patients aged 50 years or above and 738 cells/μL (IQR 548-1002) in patients aged 18-35 years. The differences in the percentage of subjects achieving sufficient immune reconstitution (CD4+ T-cell count 〉  500 cells/μL) between the two age groups were 15, 21 and 26% at year 1, 4 years and steady state, respectively, suggesting that advanced age may have a greater impact on long-term CD4+ T-cell recovery.
    Type of Medium: Online Resource
    ISSN: 1742-4933
    URL: Article
    DOI: 10.1186/s12979-021-00260-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2168941-6
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  • 7
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    Signatures of divergent anti-malarial treatment responses in peripheral blood from adults and young children in Malawi
    Springer Science and Business Media LLC ; 2019
    In:  Malaria Journal Vol. 18, No. 1 ( 2019-12)
    Details
    In: Malaria Journal, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2019-12)
    Type of Medium: Online Resource
    ISSN: 1475-2875
    URL: Article
    DOI: 10.1186/s12936-019-2842-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2091229-8
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  • 8
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    Immunologic, Virologic, and Pharmacologic Characterization of the Female Upper Genital Tract in HIV-Infected Women
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  JAIDS Journal of Acquired Immune Deficiency Syndromes Vol. 68, No. 4 ( 2015-04-1), p. 420-424
    Details
    In: JAIDS Journal of Acquired Immune Deficiency Syndromes, Ovid Technologies (Wolters Kluwer Health), Vol. 68, No. 4 ( 2015-04-1), p. 420-424
    Type of Medium: Online Resource
    ISSN: 1525-4135
    URL: Article
    DOI: 10.1097/QAI.0000000000000480
    RVK:
    XA 10000
    RVK:
    XA 51942
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 2038673-4
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  • 9
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    Maternal HIV-1 Env Vaccination for Systemic and Breast Milk Immunity To Prevent Oral SHIV Acquisition in Infant Macaques
    American Society for Microbiology ; 2018
    In:  mSphere Vol. 3, No. 1 ( 2018-02-28)
    Details
    In: mSphere, American Society for Microbiology, Vol. 3, No. 1 ( 2018-02-28)
    Abstract: Mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) contributes to an estimated 150,000 new infections annually. Maternal vaccination has proven safe and effective at mitigating the impact of other neonatal pathogens and is one avenue toward generating the potentially protective immune responses necessary to inhibit HIV-1 infection of infants through breastfeeding. In the present study, we tested the efficacy of a maternal vaccine regimen consisting of a modified vaccinia virus Ankara (MVA) 1086.C gp120 prime-combined intramuscular-intranasal gp120 boost administered during pregnancy and postpartum to confer passive protection on infant rhesus macaques against weekly oral exposure to subtype C simian-human immunodeficiency virus 1157ipd3N4 (SHIV1157ipd3N4) starting 6 weeks after birth. Despite eliciting a robust systemic envelope (Env)-specific IgG response, as well as durable milk IgA responses, the maternal vaccine did not have a discernible impact on infant oral SHIV acquisition. This study revealed considerable variation in vaccine-elicited IgG placental transfer and a swift decline of both Env-specific antibodies (Abs) and functional Ab responses in the infants prior to the first challenge, illustrating the importance of pregnancy immunization timing to elicit optimal systemic Ab levels at birth. Interestingly, the strongest correlation to the number of challenges required to infect the infants was the percentage of activated CD4 + T cells in the infant peripheral blood at the time of the first challenge. These findings suggest that, in addition to maternal immunization, interventions that limit the activation of target cells that contribute to susceptibility to oral HIV-1 acquisition independently of vaccination may be required to reduce infant HIV-1 acquisition via breastfeeding. IMPORTANCE Without novel strategies to prevent mother-to-child HIV-1 transmission, more than 5% of HIV-1-exposed infants will continue to acquire HIV-1, most through breastfeeding. This study of rhesus macaque dam-and-infant pairs is the first preclinical study to investigate the protective role of transplacentally transferred HIV-1 vaccine-elicited antibodies and HIV-1 vaccine-elicited breast milk antibody responses in infant oral virus acquisition. It revealed highly variable placental transfer of potentially protective antibodies and emphasized the importance of pregnancy immunization timing to reach peak antibody levels prior to delivery. While there was no discernible impact of maternal immunization on late infant oral virus acquisition, we observed a strong correlation between the percentage of activated CD4 + T cells in infant peripheral blood and a reduced number of challenges to infection. This finding highlights an important consideration for future studies evaluating alternative strategies to further reduce the vertical HIV-1 transmission risk.
    Type of Medium: Online Resource
    ISSN: 2379-5042
    URL: Article
    DOI: 10.1128/mSphere.00505-17
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2018
    detail.hit.zdb_id: 2844248-9
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  • 10
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    A randomized clinical trial on the effects of progestin contraception in the genital tract of HIV-infected and uninfected women in Lilongwe, Malawi: Addressing evolving research priorities
    Elsevier BV ; 2017
    In:  Contemporary Clinical Trials Vol. 52 ( 2017-01), p. 27-34
    Details
    In: Contemporary Clinical Trials, Elsevier BV, Vol. 52 ( 2017-01), p. 27-34
    Type of Medium: Online Resource
    ISSN: 1551-7144
    URL: Article
    DOI: 10.1016/j.cct.2016.11.006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 2176813-4
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