Impaired hepatitis C virus-specific T cell responses and recurrent hepatitis C virus in HIV coinfection.

BACKGROUND: Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection. METHODS AND FINDINGS: We measured T cell responsiveness by lymphoproliferation and interferon-gamma ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r(2) = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8(+) T cell interferon-gamma response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = -0.94, p = 0.017). CONCLUSIONS: These results indicate that HIV infection impairs the immune response to HCV-including in persons who have cleared HCV infection-and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.

The incidence of neovascular membranes and visual field defects from optic nerve head drusen in children.

PURPOSE: To evaluate the incidence of visual field defects and choroidal neovascular membranes (CNVM) in a cohort of pediatric patients with optic nerve head drusen (ONHD). METHODS: The medical records of children with ONHD seen at a single center from January 2012 to July 2014 were retrospectively reviewed to identify patients who had a dilated fundus examination, fundus photography, spectral domain optical coherence tomography (SD-OCT)/enhanced-depth imaging (EDI) of the optic nerve head (ONH), SITA fast 24-2 Humphrey visual field (HVF) testing, lumbar puncture, and ocular ultrasound. A masked neuro-ophthalmologist analyzed fundus photographs, OCT, and fields. Retinal nerve fiber layer (RNFL) data were compared to age-matched controls. RESULTS: A total of 52 children (98 eyes) were included. Mean age was 10.8 ± 3.3 years. Of these, 42 patients had visual fields (57 eyes deemed reliable), and 19 eyes had documented visual field deficits (8 were reproducible across ≥1 sitting [frequency 14%]). After correction of plotting errors (40 eyes), RNFL thickness was 111.9 ± 17.9 µm. CNVM were present in 24 of 98 eyes (24.5%), with 21 of 24 located nasally (87.5%). Neither RNFL thinning nor identification of ONHD on fundus photography correlated with the presence of visual field defects. CONCLUSIONS: Visual field defects due to ONHD can be reliably identified in children. In eyes of children with ONHD, RNFL protocol is frequently unreliable and may overestimate RNFL thickness. EDI scans through the ONH revealed peripapillary CNVM in nearly a quarter of the patients. Further longitudinal studies looking at the progression of CNVM and visual field deficits are warranted.

A comparison of Icare PRO and Tono-Pen XL tonometers in anesthetized children.

BACKGROUND: Tonometry in the anesthetized child, vital for evaluating known or suspected glaucoma, remains limited to tonometers capable of supine recording. The Icare PRO measures intraocular pressure (IOP) in the sitting or supine patient. The purpose of this study was to compare Icare PRO and Tono-Pen tonometry during examination under anesthesia in eyes of supine children with normal eyes and glaucoma and/or corneal pathology. METHODS: In this prospective study of children undergoing examination under anesthesia, IOP was recorded in both eyes with Icare PRO and Tono-Pen immediately after mask anesthesia induction, with instrument order randomized. RESULTS: A total of 100 eyes of 50 children (median age, 58 months) were included. IOP range was 6-50 mm Hg by Icare PRO and 6-53 mm Hg by Tono-Pen. Mean IOP measured by Tono-Pen (18.9 ± 7.5) was higher than that measured by Icare PRO (16.7 ± 7.1 mm Hg) by 2.2 mm Hg (P < 0.001). The presence of corneal edema was associated with IOP measurements higher by Tono-Pen than by Icare PRO (mean difference, 8.4 mm Hg). When eyes with corneal edema were excluded from analysis, there was no correlation between central corneal thickness and the difference in IOP between the two instruments. CONCLUSIONS: IOP in eyes of supine children under anesthesia measured approximately 2 mm Hg higher by Tono-Pen than Icare PRO and this difference was greater in eyes with frank corneal edema. Icare PRO may become a valuable tool for tonometry in supine infants and children, but a confirmatory test should be considered in eyes with corneal edema.

Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution.

UNLABELLED: CD8(+) T cell responses play a key role in governing the outcome of hepatitis C virus (HCV) infection, and viral evolution enabling escape from these responses may contribute to the inability to resolve infection. To more comprehensively examine the extent of CD8 escape and adaptation of HCV to human leukocyte antigen (HLA) class I restricted immune pressures on a population level, we sequenced all non-structural proteins in a cohort of 70 chronic HCV genotype 1a-infected subjects (28 subjects with HCV monoinfection and 42 with HCV/human immunodeficiency virus [HIV] coinfection). Linking of sequence polymorphisms with HLA allele expression revealed numerous HLA-associated polymorphisms across the HCV proteome. Multiple associations resided within relatively conserved regions, highlighting attractive targets for vaccination. Additional mutations provided evidence of HLA-driven fixation of sequence polymorphisms, suggesting potential loss of some CD8 targets from the population. In a subgroup analysis of mono- and co-infected subjects some associations lost significance partly due to reduced power of the utilized statistics. A phylogenetic analysis of the data revealed the substantial influence of founder effects upon viral evolution and HLA associations, cautioning against simple statistical approaches to examine the influence of host genetics upon sequence evolution of highly variable pathogens. CONCLUSION: These data provide insight into the frequency and reproducibility of viral escape from CD8(+) T cell responses in human HCV infection, and clarify the combined influence of multiple forces shaping the sequence diversity of HCV and other highly variable pathogens.

Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes.

A vigorous hepatitis C virus (HCV)-specific Th cell response is regarded as essential to the immunological control of HCV viremia. The aim of this study was to comprehensively define the breadth and specificity of dominant HCV-specific CD4(+) T cell epitopes in large cohorts of subjects with chronic and spontaneously resolved HCV viremia. Following in vitro stimulation of PBMC, HCV-specific cell cultures from each subject were screened with an overlapping panel of synthetic 20-mer peptides spanning the entire HCV polyprotein. Of 22 subjects who spontaneously controlled HCV viremia, all recognized at least one of a group of six epitopes situated within the nonstructural (NS) proteins NS3, NS4, and NS5, each of which was detected by >30% of subjects, but most subjects recognized additional, more heterogeneous specificities. In contrast, none of the most frequently targeted epitopes was detected by >5% of persons with chronic infection. The most frequently recognized peptides showed promiscuous binding to multiple HLA-DR molecules in in vitro binding assays and were restricted by different HLA-DR molecules in functional assays in different persons. These data demonstrate that predominant CD4(+) T cell epitopes in persons with resolved HCV infection are preferentially located in the nonstructural proteins and are immunogenic in the context of multiple class II molecules. This comprehensive characterization of CD4(+) T cell epitopes in resolved HCV infection provides important information to facilitate studies of immunopathogenesis and HCV vaccine design and evaluation.

The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1.

CD8(+) T-cell responses are an essential antiviral host defense in persistent viral infections, and their sustained effectiveness is thought to be critically dependent on CD4(+) T-helper cells. To determine the relationship between HIV-1-induced CD4(+) T-cell depletion and hepatitis C virus (HCV)-specific CD8(+) T-cell responses during viral persistence, we studied 103 persons positive for HCV, 74 coinfected with HIV-1. CD8(+) T-cell responses to the entire HCV polyprotein were determined by using an interferon-gamma enzyme-linked immunospot (ELISpot) assay. Although HIV-1 infection by itself was not associated with a diminished HCV-specific response, HIV-1-associated CD4(+) depletion was associated with significantly lower HCV-specific CD8(+) T cells (R = 0.48, P < .0001). In contrast, declining CD4(+) counts over the same range were not associated with diminished Epstein-Barr virus (EBV)- (R = 0.19, P = .31) or HIV-1-specific (R = -0.13, P = .60) CD8(+) T-cell responses in persons infected with all viruses. These data indicate that frequencies of circulating HCV-specific CD8(+) T-cell responses are sensitive to absolute CD4(+) T-cell counts and provide a possible explanation for the accelerated HCV disease course in persons coinfected with HIV-1 and HCV.