Early Hepatitis C Virus Infection Research Articles

Comparison of effectiveness and cost of different HCV testing strategies in high-risk populations in China.

High-risk populations are the predominant populations affected by hepatitis C virus(HCV) infection, and there is an urgent need for efficient and cost-effective HCV testing strategies for high-risk populations to identify potential undiagnosed HCV-infectedindividuals. This study compared several commonly used testing strategies and conducted effectiveness and cost analysis to select the appropriate testing strategy for diagnosing HCV infection in high-risk populations. Among the 2093 samples from high-risk populations in this study, 1716 were HCV negative, 237 were current HCV infection, 137 were past HCV infection, and three were acute early HCV infection. It was found that out of 237 patients with HCV current infection, Strategy A could detect 225 cases, with a missed detection rate of 5.06%, and the total cost was 33 299 RMB. In addition, Strategy B could detect 237 cases of current HCV infection, and the HCV missed detection rate was 0.00%, and the total cost was 147 221 RMB. While 137 cases of past HCV infection could be distinguished by strategy C, but 14 cases with current HCV infection were missed, with an HCV-positivemissed detection rate of 5.91%, and the total cost for Strategy C was 43 059 RMB. In conclusion, in high-risk populations, the HCV positivity rate is typically higher. If feasible, the preferred approach is to directly conduct HCV RNA testing, which effectively minimizes the risk of missing cases. However, in situations with limited resources, it is advisable to initially choose a highly sensitive method for anti-HCV screening, followed by HCV RNA testing on reactive samples.

Global Lipidome Profiling Revealed Multifaceted Role of Lipid Species in Hepatitis C Virus Replication, Assembly, and Host Antiviral Response.

Hepatitis C virus (HCV) is a major human pathogen that requires a better understanding of its interaction with host cells. There is a close association of HCV life cycle with host lipid metabolism. Lipid droplets (LDs) have been found to be crucial organelles that support HCV replication and virion assembly. In addition to their role in replication, LDs also have protein-mediated antiviral properties that are activated during HCV infection. Studies have shown that HCV replicates well in cholesterol and sphingolipid-rich membranes, but the ways in which HCV alters host cell lipid dynamics are not yet known. In this study, we performed a kinetic study to check the enrichment of LDs at different time points of HCV infection. Based on the LD enrichment results, we selected early and later time points of HCV infection for global lipidomic study. Early infection represents the window period for HCV sensing and host immune response while later infection represents the establishment of viral RNA replication, virion assembly, and egress. We identified the dynamic profile of lipid species at early and later time points of HCV infection by global lipidomic study using mass spectrometry. At early HCV infection, phosphatidylinositol phospholipids (PIPs), lysophosphatidic acid (LPA), triacyl glycerols (TAG), phosphatidylcholine (PC), and trihexosylceramides (Hex3Cer) were observed to be enriched. Similarly, free fatty acids (FFA), phosphatidylethanolamine (PE), N-acylphosphatidylethanolamines (NAPE), and tri acylglycerols were enriched at later time points of HCV infection. Lipids enriched at early time of infection may have role in HCV sensing, viral attachment, and immune response as LPA and PIPs are important for immune response and viral attachment, respectively. Moreover, lipid species observed at later infection may contribute to HCV replication and virion assembly as PE, FFA, and triacylglycerols are known for the similar function. In conclusion, we identified lipid species that exhibited dynamic profile across early and later time points of HCV infection compared to mock cells, which could be therapeutically relevant in the design of more specific and effective anti-viral therapies.

HCV-Induced Immunometabolic Crosstalk in a Triple-Cell Co-Culture Model Capable of Simulating Systemic Iron Homeostasis.

Iron is crucial to the regulation of the host innate immune system and the outcome of many infections. Hepatitis C virus (HCV), one of the major viral human pathogens that depends on iron to complete its life cycle, is highly skilled in evading the immune system. This study presents the construction and validation of a physiologically relevant triple-cell co-culture model that was used to investigate the input of iron in HCV infection and the interplay between HCV, iron, and determinants of host innate immunity. We recorded the expression patterns of key proteins of iron homeostasis involved in iron import, export and storage and examined their relation to the iron regulatory hormone hepcidin in hepatocytes, enterocytes and macrophages in the presence and absence of HCV. We then assessed the transcriptional profiles of pro-inflammatory cytokines Interleukin-6 (IL-6) and interleukin-15 (IL-15) and anti-inflammatory interleukin-10 (IL-10) under normal or iron-depleted conditions and determined how these were affected by infection. Our data suggest the presence of a link between iron homeostasis and innate immunity unfolding among liver, intestine, and macrophages, which could participate in the deregulation of innate immune responses observed in early HCV infection. Coupled with iron-assisted enhanced viral propagation, such a mechanism may be important for the establishment of viral persistence and the ensuing chronic liver disease.

Prospective Multicenter Study of Early Antiviral Therapy in Liver and Kidney Transplant Recipients of HCV-Viremic Donors.

Organs from hepatitis C virus (HCV)-viremic donors have been used in HCV-uninfected recipients (D+/R-), but the optimal treatment approach has not been defined. We evaluated the kinetics of HCV infection following transplant in D+/R- kidney-transplant (KT) and liver-transplant (LT) recipients when a preemptive antiviral strategy was used. Six US transplant programs prospectively treated D+/R- primary LT and KT recipients with sofosbuvir-velpastasvir for 12weeks starting once viremia was confirmed following transplant and the patients were judged to be clinically stable, including estimated glomerular filtration rate >30mL/min. Primary endpoints were sustained virologic response at 12weeks following transplant and safety (assessed by proportion of treatment-related adverse and serious adverse events). Of the 24 patients transplanted (13 liver, of whom 2 had prior-treated HCV infection; 11 kidney), 23 became viremic after transplant. The median (interquartile range) time from transplant to start of antiviral therapy was 7.0 (6.0, 12.0) versus 16.5 (9.8, 24.5) days, and the median (interquartile range) HCV-RNA level 3days after transplant was 6.5 (3.9, 7.1) versus 3.6 (2.9, 4.0) log10 IU/mL in LT versus KT recipients, respectively. By week 4 of treatment, 10 of 13 (77%) LT, but only 2 of 10 (20%) KT, had undetectable HCV RNA (P=0.01). At the end of treatment, all LT recipients were HCV RNA-undetectable, whereas 3 (30%) of the kidney recipients still had detectable, but not quantifiable, viremia. All achieved sustained virologic response at 12weeks following transplant (lower 95% confidence interval bound: 85%). Serious adverse events considered possibly related to treatment were antibody-mediated rejection, biliary sclerosis, cardiomyopathy, and graft-versus-host disease, with the latter associated with multiorgan failure, premature treatment discontinuation, and death. Despite differing kinetics of early HCV infection in liver versus non-liver recipients, a preemptive antiviral strategy is effective. Vigilance for adverse immunologic events is warranted.

Assessing routes of hepatitis C transmission in HIV-infected men who have sex with men using single genome sequencing.

The epidemic of hepatitis C virus (HCV) infection among HIV-infected men who have sex with men (MSM) is in its second decade, but the routes of transmission remain poorly understood. We hypothesized that by pairing single genome sequencing (SGS), to enumerate infecting HCV genomes (viruses), with detailed sexual and drug histories, we could gain insight into the routes of transmission among MSM. We used SGS to analyze blood specimens from eight HIV-infected MSM who had 10 episodes of acute (seronegative) or early HCV infections. Seven of eight men reported condomless receptive anal intercourse (CRAI), six with rectal exposure to semen, and all eight denied rectal trauma or bleeding. Of the 10 HCV infections, eight resulted from transmission of a single virus; one infection resulted from transmission of either one or a few (three or four) closely-related viruses; and one infection resulted from transmission of >10 distinct viruses. The participant infected by >10 viruses reported sharing injection equipment for methamphetamine during sex. Two other participants also injected methamphetamine during sex but they did not share injection equipment and were infected by a single virus. Conclusions: Most HCV infections of HIV-infected MSM without a history of either rectal trauma or bleeding or shared injection equipment were caused by a single virus. Intra-rectal exposure to semen during CRAI is therefore likely sufficient for HCV transmission among MSM. Conversely, rectal trauma or bleeding or shared injection equipment are not necessary for HCV transmission among MSM. These results help clarify routes of HCV transmission among MSM and can therefore help guide the design of much-needed behavioral and other interventions to prevent HCV transmission among MSM.

Envelope-Specific IgG3 and IgG1 Responses Are Associated with Clearance of Acute Hepatitis C Virus Infection.

Hepatitis C virus (HCV) can be cleared naturally in a subset of individuals. However, the asymptomatic nature of acute HCV infection makes the study of the early immune response and defining the correlates of protection challenging. Despite this, there is now strong evidence implicating the humoral immune response, specifically neutralising antibodies, in determining the clearance or chronicity outcomes of primary HCV infection. In general, immunoglobulin G (IgG) plays the major role in viral neutralisation. However, there are limited investigations of anti-HCV envelope protein 2 (E2) isotypes (IgM, IgG, IgA) and IgG subclasses (IgG1–4) in early HCV infection. In this study, using a rare cohort of 14 very recently HCV-infected individuals (4–45 days) with varying disease outcome (n = 7 clearers), the timing and potency of anti-HCV E2 isotypes and IgG subclasses were examined longitudinally, in relation to neutralising antibody activity. Clearance was associated with anti-E2 IgG, specifically IgG1 and IgG3, and appeared essential to prevent the emergence of new HCV variants and the chronic infection outcome. Interestingly, these IgG responses were accompanied by IgM antibodies and were associated with neutralising antibody activity in the subjects who cleared infection. These findings provide novel insights into the early humoral immune response characteristics associated with HCV disease outcome.

Seronegative hepatitis C virus infection in Polish blood donors-Virological characteristics of index donations and follow-up observations.

Nucleic acid testing (NAT) was implemented in Poland in 1999 for screening of plasma for fractionation and for all blood donors in 2002. To analyze seronegative NAT‐positive samples representing hepatitis C virus (HCV) window‐period (WP) in the years 2000 to 2016 and to determine infection outcome. We analyzed results of 17 502 739 donations screened in minipools (6‐48) or individually. Index samples underwent viral load (VL) quantification, genotyping and Ag, and anti‐HCV re‐testing using chemiluminescence (CMIA), electrochemiluminescence (ECLIA), and fourth‐generation enzyme‐linked immunosorbent assay (IV EIA) assays. HCV‐seronegative infections were identified in 126 donations (7.2/mln donations; 95% confidential intervals, 6.0‐8.6). Frequency of NAT yields was decreasing over time. Of the initial 126 seronegative index cases 106 were retested: 32.1% were reactive in IV EIA, 11.3% in ECLIA, and 1.9% in CMIA. The lowest VL correlated with absent anti‐HCV and HCV Ag, while VL was highest when the antigen was detectable and then it decreased when anti‐HCV appeared at a level detectable by sensitive third generation tests while retesting. The proportion of genotype 1 was 38.9% in samples positive only for HCV RNA and 71.4% in samples that were anti‐HCV reactive in re‐testing. In parallel, genotype 3 frequency was 50% in the former group and 21% in the latter. NAT is an effective measure to limit HCV transmission by transfusion and IV EIA seems to have higher clinical sensitivity than ECLIA. Samples representing likely successive phases of early HCV infection were characterized by different genotype distribution probably due to very early elimination of genotype 3.

Anal Dysplasia in Human Immunodeficiency Virus-Infected Men Who Have Sex With Men With Sexually Acquired Early Hepatitis C Virus Infection.

BackgroundHuman immunodeficiency virus (HIV)-infected men who have sex with men (MSM) are at increased risk of anorectal infection with high-risk human papillomavirus and subsequent high-grade squamous intraepithelial lesions (HSIL), the putative precursor to anal cancer. Recently, an epidemic of sexually transmitted hepatitis C virus (HCV) has emerged that shares this anorectal route of transmission. We hypothesized that the prevalence of anal HSIL would be high in HIV-infected MSM with sexually acquired early HCV infection.MethodsHigh-resolution anoscopy (HRA) findings from a cohort of HIV-infected MSM with sexually acquired early HCV infection were compared with HRA findings from a contemporary cohort of HIV-infected MSM without HCV infection who underwent HRA due to abnormal anal cytology found during routine screening.ResultsSixty HIV-infected MSM with sexually acquired early HCV infection and the comparator group of 1150 HIV-infected MSM with abnormal anal cytology but without HCV underwent HRA. The HIV-infected MSM with sexually acquired early HCV had higher CD4 counts compared with the comparator group (656 and 541 cells/μL, respectively; P = .02). Despite this, the prevalence of anal dysplasia was as high among MSM with early HCV as in the comparator group of MSM with abnormal cytology (47 [78%] and 941 [82%], respectively; P = .50), as was the proportion with HSIL (25 [42%] and 379 [33%], respectively; P = .17).ConclusionsThe prevalence of anal dysplasia in HIV-infected MSM with sexually acquired early HCV infection was as high as that of HIV-infected MSM with abnormal anal cytology. These findings suggest that primary screening with HRA may be warranted for HIV-infected MSM with early HCV.

Clearance of hepatitis C virus is associated with early and potent but narrowly-directed, Envelope-specific antibodies

Hepatitis C virus (HCV) is one of very few viruses that are either naturally cleared, or alternatively persist to cause chronic disease. Viral diversity and escape, as well as host adaptive immune factors, are believed to control the outcome. To date, there is limited understanding of the critical, early host-pathogen interactions. The asymptomatic nature of early HCV infection generally prevents identification of the transmitted/founder (T/F) virus, and thus the study of host responses directed against the autologous T/F strain. In this study, 14 rare subjects identified from very early in infection (4–45 days) with varied disease outcomes (n = 7 clearers) were examined in regard to the timing, breadth, and magnitude of the neutralizing antibody (nAb) response, as well as evolution of the T/F strain. Clearance was associated with earlier onset and more potent nAb responses appearing at a mean of 71 days post-infection (DPI), but these responses were narrowly directed against the autologous T/F virus or closely related variants. In contrast, a delayed onset of nAbs (mean 425 DPI) was observed in chronic progressors that appear to have targeted longitudinal variants rather than the T/F strain. The nAb responses in the chronic progressors mapped to known CD81 binding epitopes, and were associated with rapid emergence of new viral variants with reduced CD81 binding. We propose that the prolonged period of viremia in the absence of nAbs in these subjects was associated with an increase in viral diversity, affording the virus greater options to escape nAb pressure once it emerged. These findings indicate that timing of the nAb response is essential for clearance. Further investigation of the specificities of the early nAbs and the factors regulating early induction of protective nAbs is needed.

Covering the Cover

Covering the Cover

Hepatitis C Virus as a Unique Human Model Disease to Define Differences in the Transcriptional Landscape of T Cells in Acute versus Chronic Infection.

The hepatitis C virus is unique among chronic viral infections in that an acute outcome with complete viral elimination is observed in a minority of infected patients. This unique feature allows direct comparison of successful immune responses with those that fail in the setting of the same human infection. Here we review how this scenario can be used to achieve better understanding of transcriptional regulation of T-cell differentiation. Specifically, we discuss results from a study comparing transcriptional profiles of hepatitis C virus (HCV)-specific CD8 T-cells during early HCV infection between patients that do and do not control and eliminate HCV. Identification of early gene expression differences in key T-cell differentiation molecules as well as clearly distinct transcriptional networks related to cell metabolism and nucleosomal regulation reveal novel insights into the development of exhausted and memory T-cells. With additional transcriptional studies of HCV-specific CD4 and CD8 T-cells in different stages of infection currently underway, we expect HCV infection to become a valuable model disease to study human immunity to viruses.

Ledipasvir and Sofosbuvir in the Treatment of Early Hepatitis C Virus Infection in HIV-Infected Men.

BackgroundTreatment of HIV-infected men during early hepatitis C virus (HCV) infection with interferon results in a higher cure rate with a shorter duration of treatment than during chronic HCV infection. We recently demonstrated that this phenomenon applied to interferon-free treatment as well, curing most participants with short-course sofosbuvir and ribavirin. Due to the significantly higher potency of the ledipasvir/sofosbuvir (LDV/SOF) combination, we hypothesized that we would be more successful in curing early HCV infections using a shorter course of LDV/SOF than that used for treating chronic HCV infections.MethodsWe performed a prospective, open-label, consecutive case series study of 8 weeks of LDV/SOF in HIV-infected men with early genotype 1 HCV infection. The primary end point was aviremia at least 12 weeks after completion of treatment.ResultsWe treated 25 HIV-infected men with early sexually acquired HCV infection with 8 weeks of LDV/SOF, and all 25 (100%) were cured. Twelve (48%) reported sexualized drug use with methamphetamine.ConclusionsEight weeks of LDV/SOF cured all 25 HIV-infected men with early HCV infection, including those who were actively using drugs. Based on these results, we recommend treatment of newly HCV-infected men during early infection, regardless of drug use, to both take advantage of this 8-week treatment and to decrease further HCV transmission among this group of men.

Depression, fatigue and neurocognitive deficits in chronic hepatitis C.

Patients with chronic hepatitis C virus (HCV) infection experience a range of symptoms including depression, fatigue and neurocognitive deficits, impairing quality of life. Depression, in particular, may be reactive to increased psychosocial stress, and the physical symptoms of advanced HCV or associated comorbidities. However, even patients at an early stage of HCV infection, with minimal hepatic inflammation or comorbidities, report more depressive symptoms and fatigue than the general population. Similarly, specific neurocognitive deficits occur in early stage HCV infection and are independent of the presence of depression or encephalopathy. Therefore, intracerebral neurobiological changes associated with HCV may potentially explain these symptoms. These changes may arise from infiltration of the brain by peripherally induced cytokines, as well as direct neuropathic effects of HCV viral particles penetrating the blood-brain barrier. These phenomena parallel those reported in human immunodeficiency virus (HIV) infection. HCV-associated intracerebral changes include upregulated inflammatory responses, altered neurotransmitter levels, hormonal dysregulation, and release of neurotoxic substances. These may subsequently lead to abnormal neuronal conduction and function in areas of the brain governing affective responses, emotional processing, motivation, attention and concentration. Although direct-acting antiviral medications lead to high rates of HCV clearance, intracerebral changes may not be subsequently reversed and symptoms of depression, fatigue and neurocognitive deficits may persist. There is an ongoing role for multidisciplinary care and pharmacotherapy to manage these symptoms in HCV patients. Furthermore, there may be opportunities for future therapies to specifically target and ameliorate HCV-associated intracerebral changes.

Sofosbuvir in the treatment of early HCV infection in HIV-infected men

Background: There is an international epidemic of hepatitis C virus (HCV) infection among HIV-infected men who have sex with men. We previously showed that adding telaprevir to pegylated interferon (IFN) and ribavirin (RBV) both shortened treatment and increased the cure rate of early HCV in these men. Whether shortening treatment of early HCV using IFN-free regimens would be similarly successful has not yet been demonstrated.Methods: We performed a pilot study of treatment with sofosbuvir (SOF) + RBV for 12 weeks in early genotype 1 HCV infection in HIV-infected men. The primary endpoint was SVR 12.Results: Twelve men were treated with 12 weeks SOF + RBV and 11 (92%) achieved SVR 12. Most (63%) were actively using recreational drugs, mostly methamphetamine. The one man who failed had laboratory results more characteristic of chronic than of early HCV infection. The overall safety profile was similar to that known for SOF + RBV.Conclusions: The success of this short-duration IFN-free treatment in early HCV infection is proof in principle that enhanced treatment responsiveness is an inherent characteristic of early HCV infection and not a function of IFN treatment itself. Future studies should now be done with more potent regimens to try to further shorten therapy. In the mean time, in clinical practice early HCV infection should be treated immediately after detection to take advantage of short-duration treatments, as well as to decrease further HCV transmission among HIV-infected MSM.

Dynamic evolution of hepatitis C virus resistance-associated substitutions in the absence of antiviral treatment

Resistance against new hepatitis C virus (HCV) antivirals is an area of increasing interest. Resistance-associated substitutions (RASs) have been identified in treatment-naïve individuals, but pressures driving treatment-independent RAS emergence are poorly understood. We analysed the longitudinal evolution of RASs in twelve participants with early acute HCV infections. Full-genome deep sequences were analysed for changes in RAS frequency within NS3, NS5A and NS5B-coding regions over the course of the infection. Emergence of RASs relevant only to the polymerase non-nucleoside inhibitors (NNI) was detected, and these lay within CD8+ T-cell epitopes. Conversely, the loss of NNI RASs over time appeared likely to be driven by viral fitness constraints. These results highlight the importance of monitoring CD8+ T cell epitope-associated RASs in populations with dominant HLA types.

Phylogenetic analysis of full-length, early infection, hepatitis C virus genomes among people with intravenous drug use: the InC3 Study.

Cross-continental phylogenetic analysis is important to understand subtle molecular differences of currently circulating hepatitis C virus (HCV) subtypes. Existence of such differences can be crucial in pursuing a universal hepatitis C vaccine. We characterized molecular epidemiology of early HCV infections identified across nine cohorts [North America (n=4), Australia (n=4) and Europe (n=1)] in the International Collaborative of Incident HIV and Hepatitis C in Injecting Cohorts (InC3 ). One hundred and ninety-two full-length HCV genomes were amplified from plasma of incident infections and subjected to next generation sequencing to establish the largest cross-continental, full-length acute HCV genomic data set available to date. Genomes from the most common subtypes (1a: n=94, 2b: n=15 and 3a: n=68) were used in phylogenetic analysis. Using full genome trees, 78 sequences (44%) were found to lie within 29 phylogenetic clusters/pairs defined on the basis of molecular similarity of consensus sequences. Of these, 26 each had exclusively Australian or North American sequences indicating a strong geographical bias for molecular similarity. On further analysis of behavioural and demographic associations, binary logistic regression analysis showed that older age and non-Caucasian ethnicity were significantly associated with clustering. HCV probably evolves in micro-epidemics within geographically isolated communities.

Treatment of Early Hepatitis C Infection in HIV-Infected Men—When to Treat, Whom, and with What?

There has been an expanding international epidemic of sexually transmitted hepatitis C virus (HCV) infection among HIV-infected men who have sex with men (MSM) since the turn of the twenty-first century, resulting in a progressively increasing number of these men presenting with early HCV infection in need of treatment. We and others have recently performed studies using short-course treatment with direct-acting antiviral (DAA) regimens in patients with early HCV infection that found similar or better cure rates compared to historical studies treating patients with chronic HCV. These studies provide further evidence that there is an enhanced treatment responsiveness period in early HCV infection. Ironically, since the introduction of truly safe and effective interferon-free DAA regimens, these treatments have become more difficult to obtain apparently due to higher costs, not of the price per cure, but because more people now want treatment. Prompt rather than delayed administration of treatment could further decrease the primary and re-infection rates among MSM by shortening the duration of infectiousness of these newly infected men. Since early and effective treatment of HCV infection is one of the essential elements in combating this epidemic and decreasing the number of new infections, and since short-course therapy, which is highly effective only in early HCV infection, is less expensive, we should be treating these patients immediately in this newly cost hyper-sensitive environment. We therefore urge that treatment guidelines be changed to reflect these rational arguments. Such guideline changes would additionally serve to push funding agencies to provide better access to treatment for early HCV infection.

Hepatitis C Virus Postexposure Prophylaxis in the Healthcare Worker: Why Direct-Acting Antivirals Don't Change a Thing.

Currently, 380 000-400 000 occupational exposures to blood-borne pathogens occur annually in the United States. The management for occupational HIV or hepatitis B virus exposures includes postexposure prophylaxis (PEP) when necessary; however, PEP is not recommended for hepatitis C virus (HCV) exposures. Recent approval of HCV direct-acting antivirals (DAAs) has renewed discussions as to whether these therapies could be used to prevent infection after exposure. There are no published studies addressing this question, but the prescribing of DAAs for PEP has been reported. We will discuss the differences in transmission of the 3 most common blood-borne pathogens, the natural history of early HCV infection, and the scientific rationale for PEP. In particular, we will discuss how the low feasibility of conducting an adequately powered clinical trial of DAA use for PEP and the low cost-effectiveness of such an intervention is not supportive of targeting limited resources for such use.

Historical Trends in the Hepatitis C Virus Epidemics in North America and Australia.

Bayesian evolutionary analysis (coalescent analysis) based on genetic sequences has been used to describe the origins and spread of rapidly mutating RNA viruses, such as influenza, Ebola, human immunodeficiency virus (HIV), and hepatitis C virus (HCV). Full-length subtype 1a and 3a sequences from early HCV infections from the International Collaborative of Incident HIV and Hepatitis C in Injecting Cohorts (InC3), as well as from public databases from a time window of 1977-2012, were used in a coalescent analysis with BEAST software to estimate the origin and progression of the HCV epidemics in Australia and North America. Convergent temporal trends were sought via independent epidemiological modeling. The epidemic of subtype 3a had more recent origins (around 1950) than subtype 1a (around 1920) in both continents. In both modeling approaches and in both continents, the epidemics underwent exponential growth between 1955 and 1975, which then stabilized in the late 20th century. Historical events that fuelled the emergence and spread of injecting drug use, such as the advent of intravenous medical therapies and devices, and growth in the heroin trade, as well as population mixing during armed conflicts, were likely drivers for the cross-continental spread of the HCV epidemics.

Host APOBEC3G protein inhibits HCV replication through direct binding at NS3.

Human APOBEC3G (hA3G) is a cytidine deaminase that restricts replication of certain viruses. We have previously reported that hA3G was a host restriction factor against hepatitis C virus (HCV) replication, and hA3G stabilizers showed a significant inhibitory activity against HCV. However, the molecular mechanism of hA3G against HCV remains unknown. We show in this study that hA3G’s C-terminal directly binds HCV non-structural protein NS3 at its C-terminus, which is responsible for NS3’s helicase and NTPase activity. Binding of hA3G to the C-terminus of NS3 reduced helicase activity, and therefore inhibited HCV replication. The anti-HCV mechanism of hA3G appeared to be independent of its deamination activity. Although early stage HCV infection resulted in an increase in host hA3G as an intracellular response against HCV replication, hA3G was gradually diminished after a long-term incubation, suggesting an unknown mechanism(s) that protects HCV NS3 from inactivation by hA3G. The process represents, at least partially, a cellular defensive mechanism against HCV and the action is mediated through a direct interaction between host hA3G and HCV NS3. We believe that understanding of the antiviral mechanism of hA3G against HCV might open an interesting avenue to explore hA3G stabilizers as a new class of anti-HCV agents.