Medical and Health Sciences

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Browsing Medical and Health Sciences by Subject "3-dioxygenase-1"

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    Changes in Immune Activation During Pregnancy and the Postpartum Period in Treated HIV Infection
    (Oxford University Press, 2021) Schnittman, Samuel R.; Byakwaga, Helen; Boum, Yap; Kabakyenga, Jerome; Matthews, Lynn T.; Burdo, Tricia H.; Huang, Yong; Tracy, Russell P.; Haberer, Jessica E.; Kembabazi, Annet; Kaida, Angela; Moisi, Daniela; Lederman, Michael M.; Bangsberg, David R.; Martin, Jeffrey N.; Hunt, Peter W.
    Pregnant women with HIV (PWWH) have high postpartum morbidity and mortality from infections like tuberculosis. Immunologic changes during pregnancy and postpartum periods may contribute to these risks, particularly the immunoregulatory kynurenine pathway of tryptophan catabolism, which contributes to both HIV and tuberculosis pathogenesis and increases in the early postpartum period. Women with HIV initiating antiretroviral therapy (ART) in the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort who were pregnant at enrollment or became pregnant during observation were studied (n = 54). Plasma kynurenine/tryptophan (KT) ratio, soluble CD14 (sCD14), sCD163, sCD27, interferon-inducible protein 10 (IP-10), D-dimer, interleukin-6, and intestinal fatty-acid binding protein levels were assessed through the first year of ART and at 3-month intervals throughout pregnancy and 1 year postpartum. Biomarker changes were assessed with linear mixed models adjusted for ART duration. Hemoglobin concentration changes were used to estimate pregnancy-related changes in plasma volume. Results. The median pre-ART CD4 count was 134. D-dimer increased through the third trimester before returning to baseline postpartum, while most other biomarkers declined significantly during pregnancy, beyond what would be expected from pregnancy associated plasma volume expansion. IP-10 and sCD14 remained suppressed for at least 12 months postpartum. KT ratio was the only biomarker that increased above prepregnancy baseline postpartum (mean + 30%; P < .001) and remained higher than baseline for ≥9 months (P ≤ .045 for all time points). Several immune activation markers decline during pregnancy and remain suppressed postpartum, but the kynurenine pathway of tryptophan catabolism increases above baseline for ≥9 months postpartum. The mechanisms underlying postpartum kynurenine pathway activity are incompletely understood but may contribute to increased tuberculosis risk in this setting.
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    The Kynurenine Pathway of Tryptophan Catabolism, CD4+ T-Cell Recovery, and Mortality Among HIV-Infected Ugandans Initiating Antiretroviral Therapy
    (The Journal of infectious diseases, 2014) Byakwaga, Helen; Boum, Yap; Huang, Yong; Muzoora, Conrad; Kembabazi, Annet; Weiser, Sheri D.; Bennett, John; Cao, Huyen; Haberer, Jessica E.; Deeks, Steven G.; Bangsberg, David R.; McCune, Joseph M.; Martin, Jeffrey N.; Hunt, Peter W.
    Human immunodeficiency virus (HIV) infection–induced indoleamine 2,3-dioxygenase-1 (IDO) expression in activated monocytes and dendritic cells catabolizes tryptophan to kynurenine and other downstream catabolites that inhibit T-cell proliferation and interleukin 17 (IL-17) production. The prognostic significance of this pathway in treated HIV disease is unknown. We measured systemic IDO activity (calculated as the ratio of plasma levels of kynurenine to tryptophan; hereafter, the “KT ratio”) in HIV-infected Ugandans before and during antiretroviral therapy (ART)–mediated viral suppression and its association with the rate of subsequent CD4+ T-cell count recovery and mortality. Among 435 participants, a higher pre-ART KT ratio was associated with a higher plasma virus load (P < .001) and lipopolysaccharide level (P = .018), a lower CD4+ T-cell count (P < .001), and female sex (P = .047). Through month 12 of ART-mediated viral suppression, the plasma KT ratio decreased by approximately 50% (P < .001). After adjustment for pre-ART CD4+ T-cell count, virus load, age, and sex, a higher month 12 KT ratio predicted a slower rate of subsequent CD4+ T-cell count recovery (P = .001). Thirty-nine participants died. After adjustment for pre-ART CD4+ T-cell count, virus load, body mass index, sex, and age, a higher pre-ART and month 6 KT ratio predicted increased mortality (P ≤ .016). The kynurenine pathway of tryptophan catabolism independently predicts poor CD4+ T-cell count recovery and increased mortality among HIV-infected Ugandans initiating ART and may be an important target for interventions.
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    Reversal of the Kynurenine Pathway of Tryptophan Catabolism May Improve Depression in ART-Treated HIV-Infected Ugandans
    (Journal of acquired immune deficiency syndromes, 2014) Martinez, Priscilla; Tsai, Alexander C.; Muzoora, Conrad; Kembabazi, Annet; Weiser, Sheri D.; Huang, Yong; Haberer, Jessica E.; Martin, Jeffrey N.; Bangsberg, David R.; Hunt, Peter W.
    Major depressive disorder is highly prevalent among HIV-infected persons, and depression symptom severity improves during the course of HIV antiretroviral therapy (ART). The potential biologic pathways explaining these phenomena remain unclear. We investigated the extent to which ART-mediated suppression of the kynurenine pathway of tryptophan catabolism (via indoleamine 2,3- dioxygenase-1 and potentially other sources) may correlate with improvements in depression symptom severity in this setting.