Vertical Transmission of Hepatitis C Virus: Variable Transmission Bottleneck and Evidence of Midgestation In Utero Infection

Abstract

Hepatitis C virus (HCV) can be transmitted from mother to child during pregnancy and childbirth. However, the timing and precise biological mechanisms that are involved in this process are incompletely understood, as are the determinants that influence transmission of particular HCV variants. Here we report results of a longitudinal assessment of HCV quasispecies diversity and composition in 5 cases of vertical HCV transmission, including 3 women coinfected with human immunodeficiency virus type 1 (HIV-1). The population structure of HCV variant spectra based on E2 envelope gene sequences (nucleotide positions 1491 to 1787), including hypervariable regions 1 and 2, was characterized using next-generation sequencing and median-joining network analysis. Compatible with a loose transmission bottleneck, larger numbers of shared HCV variants were observed in the presence of maternal coinfection. Coalescent Bayesian Markov chain Monte Carlo simulations revealed median times of transmission between 24.9 weeks and 36.1 weeks of gestation, with some confidence intervals ranging into the 1st trimester, considerably earlier than previously thought. Using recombinant autologous HCV pseudoparticles, differences were uncovered in HCV-specific antibody responses between coinfected mothers and mothers infected with HCV alone, in whom generalized absence of neutralization was observed. Finally, shifts in HCV quasispecies composition were seen in children around 1 year of age, compatible with the disappearance of passively transferred maternal immunoglobulins and/or the development of HCVspecific humoral immunity. Taken together, these results provide insights into the timing, dynamics, and biologic mechanisms involved in vertical HCV transmission and inform preventative strategies.IMPORTANCE Although it is well established that hepatitis C virus (HCV) can be transmitted from mother to child, the manner and the moment at which transmission operates have been the subject of conjecture. By carrying out a detailed examination of viral sequences, we showed that transmission could take place comparatively early in pregnancy. In addition, we showed that when the mother also carried human immunodeficiency virus type 1 (HIV-1), many more HCV variants were shared between her and her child, suggesting that the mechanism and/or the route of transmission of HCV differed in the presence of coinfection with HIV-1. These results

Hepatitis B and C viruses’ infection and associated factors among pregnant women in the Amhara region, Ethiopia: implications for prevention of vertical transmission.

“…HCV is transmitted mainly through parenteral routes such as infected blood transfusion, intravenous drug use or blood product, therapeutic injection, intravenous drug use, acupuncture, tattooing, ear piercing and transmission during sexual contact and vertically from infected-mother-to-child [5,11,12].Vertical transmission of HCV from mother-to-child contributes to 10% of cases and lower than other viral pathogens such as HIV and HBV [13]. Drugs like direct-acting antiviral agents (DAA) are effective for curing up to 70% of HCV-infected persons; however, contraindicated during pregnancy [11,13]. Currently, there is no effective vaccine for HCV and no effective means of preventing MTCT of HCV.…”

HCV in Women and Pregnancy

“…These findings are limited, due to challenges in follow-up; in a large US city, only 5% of infants born to HCVpositive mothers received appropriate testing. (41) The timing of vertical transmission can vary from midgestation (in utero) (42) to the time of delivery. (43) Peripartum transmission is believed to be due to infant exposure to infected blood or body fluids, whereas in utero transmission is influenced by immune-modulating effects of pregnancy, with loss of selective pressure on viral replication and associated increased proliferation of viral quasispecies with optimized replicative fitness.…”

Hepatitis C in Pregnancy: A Unique Opportunity to Improve the Hepatitis C Cascade of Care

“…One study evaluated HCV‐exposed neonates and found them to have lower levels of regulatory T cells and rates of clusters of differentiation (CD)4+ and CD8+ T‐cell activation as well as lower plasma levels of proinflammatory markers than controls, suggesting a relative suppression of immune activation in neonates exposed to HCV . Another study suggested that HCV can be transmitted to the neonate as early as the first trimester, especially in women coinfected with HIV, which would potentially have implications on early organ development . Early transmission would potentially lead to long‐term tolerance to HCV antigens and loss of pathogen‐specific immune competence, although there are limited clinical data to support this.…”

“…(38) Another study suggested that HCV can be transmitted to the neonate as early as the first trimester, especially in women coinfected with HIV, which would potentially have implications on early organ development. (39) Early transmission would potentially lead to long-term tolerance to HCV antigens and loss of pathogen-specific immune competence, although there are limited clinical data to support this. (29) Abbreviations: C-section, cesarean section; CVS, chorionic villus sampling; ROM, rupture of membranes.…”