Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses

Honegger, Jonathan R.; Kim, Seungtaek; Price, Aryn A; Kohout, Jennifer A; McKnight, Kevin L.; Prasad, Mona; Lemon, Stanley M.; Grakoui, Arash; Walker, Christopher M.

doi:10.1038/nm.3351

Cited by 58 publications

(84 citation statements)

References 51 publications

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“…In mice, this may not be true, as shown by fetal loss in Leishmania infection (30). However, many reports show qualitative changes in human pregnancy, including a definitive recent report studying CTL response to HCV (31). This supports clinical observations that responses to viruses such as flu and chicken pox (32,33), as well as to autoantigens, differ during pregnancy (34)(35)(36).…”

Section: T Cells In Pregnancysupporting

confidence: 59%

Uterine NK cells: active regulators at the maternal-fetal interface

Moffett¹,

Colucci²

2014

J. Clin. Invest.

338

301

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Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternalfetal immune mechanism that regulates placentation. The maternal-fetal interface in the uterusThe immunological paradox of pregnancy became a central preoccupation of immunologists after the discovery of acquired immunological tolerance (1). Pregnancy and transplantation were instrumental in the discovery of MHC polymorphisms, since the best natural producers of alloantibodies against HLA molecules are multiparous women (2) and polytransfused individuals (3). Since Medawar's influential essay (4), the focus for immunologists has been how maternal T cells become tolerant of the fetal allograft. The current state of this field has been summarized in recent scholarly reviews (5, 6). We have taken a different approach that arose from studying pregnancy disorders, which affect millions of women and are a persistent global health problem. This view of the maternal immune system arose from considering how placentation evolved in mammals and is centered on the anatomy, physiology, and pathology of the pregnant uterus. We focus on the immune cells present in the pregnant uterine lining, the decidua, dominated by NK cells (known as decidual NK cells or uterine NK

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Section: T Cells In Pregnancysupporting

confidence: 59%

Uterine NK cells: active regulators at the maternal-fetal interface

Moffett¹,

Colucci²

2014

J. Clin. Invest.

338

301

View full text Add to dashboard Cite

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“…Because of substantial variability in the pattern of epitope dominance among HCV-infected individuals, it is likely that 4x0193 exerted immune pressure against other class I-presented epitopes that have yet to be identified. Our analysis also does not account for compensatory mutations that occur outside epitopes to offset any fitness cost of immune escape to virus replication (60).…”

Section: Discussionmentioning

confidence: 99%

Evolution of a Cell Culture-Derived Genotype 1a Hepatitis C Virus (H77S.2) during Persistent Infection with Chronic Hepatitis in a Chimpanzee

Joyce

et al. 2014

J Virol

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Persistent infection is a key feature of hepatitis C virus (HCV). IMPORTANCEThis study shows that mutations promoting the production of infectious genotype 1a HCV in cell culture have the opposite effect and attenuate replication in the liver of the only fully permissive animal species other than humans. It provides the only example to date of persistent infection in a chimpanzee challenged with cell culture-produced virus and provides novel insight into the forces shaping molecular evolution of that virus during 5 years of persistent infection. It demonstrates that a poorly fit virus can replicate for weeks within the liver in the absence of detectable viremia, an observation that expands current concepts of HCV pathogenesis and that is relevant to relapses observed with direct-acting antiviral therapies.

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“…For example, multiple sclerosis symptom severity is often alleviated during pregnancy and exacerbated following delivery (10). Similarly, women persistently infected with hepatitis C virus (HCV) or hepatitis B virus (HBV) may experience a precipitous decrease in viral load in the months following delivery (11)(12)(13). Factors that contribute to the enhanced postpartum viral control are not fully understood, although in the context of HCV infection, the decrease in viral load was linked in two women to the emergence of viral variants with escape mutations in class I epitopes, suggesting a restoration of virus-specific CD8…”

mentioning

confidence: 99%

“…+ T-cell selection pressure (11). There is evidence, however, that a brief lag phase in T-cell function may occur following delivery.…”

mentioning

confidence: 99%

Prolonged activation of innate antiviral gene signature after childbirth is determined byIFNL3genotype

Price

Tedesco

Prasad

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Maternal innate and adaptive immune responses are modulated during pregnancy to concurrently defend against infection and tolerate the semiallogeneic fetus. The restoration of these systems after childbirth is poorly understood. We reasoned that enhanced innate immune activation may extend beyond gestation while adaptive immunity recovers. To test this hypothesis, the transcriptional profiles of total peripheral blood mononuclear cells following delivery in healthy women were compared with those of nonpregnant control subjects. Interestingly, interferon-stimulated genes (ISGs) encoding proteins such as IFIT1, IFIT2, and IFIT3, as well as signaling proteins such as STAT1, STAT2, and MAVS, were enriched postpartum. Antiviral genes were primarily expressed in CD14 + cells and could be stratified according to genetic variation at the interferon-λ3 gene (IFNL3, also named IL28B) SNP rs12979860. Antiviral gene expression was sustained beyond 6 mo following delivery in mothers with a CT or TT genotype, but resembled baseline nonpregnant control levels following delivery in mothers with a CC genotype. CT and TT IFNL3 genotypes have been associated with persistent elevated ISG expression in individuals chronically infected with hepatitis C virus. Together, these data suggest that postpartum, the normalization of the physiological rheostat controlling IFN signaling depends on IFNL3 genotype. postpartum | CD14 | interferon | innate immunity | antiviral genes

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Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses

Cited by 58 publications

References 51 publications

Uterine NK cells: active regulators at the maternal-fetal interface

Uterine NK cells: active regulators at the maternal-fetal interface

Evolution of a Cell Culture-Derived Genotype 1a Hepatitis C Virus (H77S.2) during Persistent Infection with Chronic Hepatitis in a Chimpanzee

Prolonged activation of innate antiviral gene signature after childbirth is determined byIFNL3genotype

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