Differing Patterns of Liver Disease Progression and Hepatitis C Virus (HCV) Quasispecies Evolution in Children Vertically Coinfected with HCV and Human Immunodeficiency Virus Type 1

Abstract

Hepatitis C virus (HCV) quasispeciation was studied in two children vertically coinfected with HCV and human immunodeficiency virus type 1 (HIV-1). HCV quasispecies diversification and liver injury were more significant in patient C1, who was immunocompetent with anti-HIV therapy, than in patient C2, who was immunosuppressed, in consistency with modulation of HCV quasispeciation and liver injury by immunocompetence in coinfected children.To characterize the evolution of hepatitis C virus (HCV) disease and the influence of human immunodeficiency virus type 1 (HIV-1) and antiretroviral therapy (ART) (17), longitudinal sequence analysis of E2 envelope gene hypervariable region 1 (HVR1) was undertaken for two male Caucasian children (C1 and C2), who acquired HCV and HIV-1 infection by mother-to-child transmission.Patient C1, born in 1996, was treated from birth with zidovudine, which was complemented with lamivudine when HIV-1 cocultures became positive at 6 weeks of age. Early HIV-1 viremia correlated with a rise in CD8 cell counts, a sharp decline in CD4 counts, and an inversion of the CD4:CD8 ratio, consistent with acute HIV-1 infection ( Fig. 1A and B) (3). HIV-1 viral load decreased and stabilized at the end of the first year of life, while CD4 counts remained within the normal range. At 1.16 years of age, combination ART (lamivudinestavudine-ritonavir) was introduced, resulting in a further decline in HIV-1 viral load and a rise in CD4 counts (Fig. 1). Levels of alanine (ALT) and aspartate (AST) aminotransferases peaked 36 days later, followed by a decline over the following weeks without a change in treatment (Fig. 1C). Infection with HCV-1b (21) at 1.77 years of age was confirmed by PCR. Stored plasma samples were used retrospectively to measure HCV RNA levels, which were not influenced by ART (Fig. 1B). Between the ages of 3 and 6, HIV-1 levels declined but remained detectable, HCV viral load was stable, ALT and AST levels remained at twice normal or less, and CD4 counts declined but remained within the normal range ( Fig. 1) (3). A liver biopsy performed at 5.83 years of age showed chronic hepatitis characterized by distorted lobular architecture together with mild, diffuse lobular inflammation with occasional nodular lymphoid infiltrate and prominent macro-and microvesicular steatosis. Portal tracts were expanded with mononuclear cell infiltrates, and interface hepatitis was present in the majority. Mild periportal and sinusoidal fibrosis was observed.At 4.5 months later, changes in ART brought the HIV-1 viral load to Ͻ50 copies/ml and raised CD4 counts. Common clinical complications related to pediatric HIV infection were not seen. HCV RNA was extracted from plasma and was amplified using previously described primers and conditions (8,9). Strict PCR precautions were adopted. A total of 115 independent subclones were sequenced. Multiple alignments were performed using Clustal X version 1.81 (30). Overall, accumulation of nucleotide substitutions was observed within HVR1 (nucleotides 1482 to 1562), while f...

Seronegative Hepatitis C Virus Infection in a Child Infected via Mother-to-Child Transmission

“…In the presence of low CD4 ϩ T cell counts and/or suboptimal antiretroviral therapy (ART), the HCV variant spectrum becomes homogenous as a result of reduced immune selective pressure exerted on HCV antigens. Conversely, when HIV-1 replication is suppressed by ART, the variant spectrum rapidly evolves and diversifies (4,28). In the present case, CVID, HIV infection, and XLA (subject is female) were all excluded as possible causes of persistent HCV seronegativity and absence of selective pressure.…”

“…However, variants isolated from CVID patients typically present with comparatively more amino acid substitutions (i.e., ϳ10) (16). Seronegative HCV infection and stable variant spectra were also observed in subjects with hepatitis C who are coinfected with HIV-1, a T-lymphotropic virus that is well known to interfere with the initiation and maintenance of humoral and cell-mediated immune responses (3,4,6,17,24,28). George et al (17) reported that CD4 ϩ T cell counts were higher in HCV-and HIV-coinfected subjects who were HCV seropositive than in coinfected subjects who were HCV seronegative despite detectable HCV RNA levels, suggestive of a relationship between the absence of HCV-specific antibody production and HIV-associated impairment of cell-mediated immunity.…”

“…The evolution of the variant spectrum or viral quasispecies profile based on this particular region of the HCV genome was associated with the spontaneous clearance of HCV infection and the transition from acute to chronic hepatitis C (11), with the response to interferon treatment (13), with the extent of liver injury (19), and with the onset of immune responses in children infected by mother-tochild transmission (22). Briefly, HCV RNA was extracted from Maternal HCV viral load in 2010 1.0 ϫ 10 7 UI per ml plasma serum using a QIAamp viral RNA minikit (Qiagen, Mississauga, Ontario, Canada) and then reverse transcribed and amplified based on previously published protocols (4,11,13,28). The PCR products were visualized on 1.7% agarose gels, purified using an agarose gel extraction kit (Feldan-bio, Quebec, Quebec, Canada), and cloned in pCR 2.1-TOPO vector (Invitrogen, Carlsbad, CA).…”

Immunité maternelle et transmission mère-enfant du VIH et du VHC

“…On sait que l'évolution clinique de l'hépatite C est modifiée durant la grossesse et après l'accouchement, et que cette modulation comporte une forte composante immunitaire [38]. On sait également que la présence du VIH et l'immunodéficience qui y est associée sont capables d'influencer la charge et la dynamique des populations virales du VHC durant la grossesse et chez l'enfant coinfecté [39][40][41]. Le traitement de choix de l'infection par le VHC, une combinaison de ribavirine et d'IFN-α pégylé, est fortement contreindiqué durant la grossesse, la ribavirine étant tératogène [42] et l'IFN-α possédant des propriétés antiprolifératives et neurotoxiques [43].…”

“…D'où l'importance d'un traitement efficace de l'infection par le VIH chez la femme co-infectée, traitement qui, en agissant directement sur la charge virale VIH et indirectement sur la reconstitution immunitaire, devrait contribuer à réduire les risques de TME du VHC. Enfin, la co-transmission du VIH et du VHC à l'enfant, bien que moins fréquente que la transmission individuelle de chacun des virus, peut avoir chez ce dernier d'importantes conséquences pathologiques à long terme [39].…”