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An AGM model for changes in complement during pregnancy: neutralization of influenza virus by serum is diminished in late third trimester.

ABSTRACT: Pregnant women in the third trimester are at increased risk of severe influenza disease relative to the general population, though mechanisms behind this are not completely understood. The immune response to influenza infection employs both complement (C') and antibody (Ab). The relative contributions of these components to the anti-viral response are difficult to dissect because most humans have pre-existing influenza-specific Abs. We developed the African green monkey (AGM) as a tractable nonhuman primate model to study changes in systemic innate immunity to influenza during pregnancy. Because the AGMs were influenza-naïve, we were able to examine the role of C' in influenza virus neutralization using serum from non-pregnant animals before and after influenza infection. We determined that serum from naïve AGMs neutralized influenza via C', while post-infection neutralization did not require C', suggesting an Ab-mediated mechanism. The latter mimicked neutralization using human serum. Further, we found that ex vivo neutralization of influenza with both naïve and influenza-immune AGM serum occurred by virus particle aggregation and lysis, with immune serum lysing virus at a much higher rate than naïve serum. We hypothesized that the anti-influenza C' response would diminish late in AGM pregnancy, corresponding with the time when pregnant women suffer increased influenza severity. We found that influenza neutralization capacity is significantly diminished in serum collected late in the third trimester. Strikingly, we found that circulating levels of C3, C3a, and C4 are diminished late in gestation relative to nonpregnant animals, and while neutralization capacity and serum C3a return to normal shortly after parturition, C3 and C4 levels do not. This AGM model system will enable further studies of the role of physiologic and hormonal changes in downregulating C'-mediated anti-viral immunity during pregnancy, and it will permit the identification of therapeutic targets to improve outcomes of influenza virus infection in pregnant women.

SUBMITTER: Mayer AE

PROVIDER: S-EPMC4237339 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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An AGM model for changes in complement during pregnancy: neutralization of influenza virus by serum is diminished in late third trimester.

Mayer Anne E AE Parks Griffith D GD

PloS one 20141119 11

Pregnant women in the third trimester are at increased risk of severe influenza disease relative to the general population, though mechanisms behind this are not completely understood. The immune response to influenza infection employs both complement (C') and antibody (Ab). The relative contributions of these components to the anti-viral response are difficult to dissect because most humans have pre-existing influenza-specific Abs. We developed the African green monkey (AGM) as a tractable nonh ...[more]

PMID: 25409303

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Project description:BackgroundThe impact of pregnancy on efavirenz (EFV) pharmacokinetics is unknown.MethodsInternational Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is an on-going, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving 600 mg EFV once daily as part of combination antiretroviral therapy. Intensive steady-state 24-hour blood sampling was performed during the third trimester and at 6-12 weeks postpartum. Maternal and umbilical cord blood samples were drawn at delivery. Pharmacokinetics targets were the estimated 10th percentile EFV area under the curve (AUC) in nonpregnant historical controls (40.0 mcg·hr(-1)·mL(-1)) and a trough concentration of 1 mcg/mL.ResultsTwenty-five women were enrolled during the third trimester: median (range) age was 29.3 (18.9-42.9) years, weight 69.0 (40-130) kg, and gestational age 32.9 (30.1-38.7) weeks. Median (range) EFV AUC(0-24), C(max), and C(24 hours) were 55.4 mcg·hr(-1)·mL(-1) (13.5-220.3), 5.4 mcg/mL (1.9-12.2), and 1.6 mcg/mL (0.23-8.13), respectively. EFV AUC and C(max) did not differ during pregnancy and postpartum but C(24 hours) was lower during the third trimester (1.6 vs. 2.1 mcg/mL, P = 0.01). During the third trimester, 5 of 25 (20%) women had an EFV AUC below the target and 3 of 25 (12%) had a trough concentration below 1 mcg/mL. EFV cord blood/maternal concentration ratio was 0.49 (0.37-0.74). All women had a HIV-1 RNA viral load less than 400 copies per milliliter at delivery and 19 (76%) had a viral load below 50 copies per milliliter. One child was perinatally HIV infected. Three women were exposed to EFV throughout the first 6 weeks of pregnancy. EFV was well tolerated, and among the 25 infants, no congenital anomalies or newborn complications were reported.ConclusionsChanges in EFV pharmacokinetics during pregnancy compared with postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.

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An AGM model for changes in complement during pregnancy: neutralization of influenza virus by serum is diminished in late third trimester.

Publications

An AGM model for changes in complement during pregnancy: neutralization of influenza virus by serum is diminished in late third trimester.

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