The absence of the human platelet antigen polymorphism effect on fibrosis progression in human immunodeficiency virus-1/hepatitis C virus coinfected patients

AbstractINTRODUCTION:Hepatic fibrosis progression in patients with chronic hepatitis C virus infections has been associated with viral and host factors, including genetic polymorphisms. Human platelet antigen polymorphisms are associated with the rapid development of fibrosis in HCV-monoinfected patients. This study aimed to determine whether such an association exists in human immunodeficiency virus-1/hepatitis C virus-coinfected patients.METHODS:Genomic deoxyribonucleic acid from 36 human immunodeficiency virus-1/hepatitis C virus-coinfected patients was genotyped to determine the presence of human platelet antigens-1, -3, or -5 polymorphisms. Fibrosis progression was evaluated using the Metavir scoring system, and the patients were assigned to two groups, namely, G1 that comprised patients with F1, portal fibrosis without septa, or F2, few septa (n = 23) and G2 that comprised patients with F3, numerous septa, or F4, cirrhosis (n = 13). Fisher's exact test was utilized to determine possible associations between the human platelet antigen polymorphisms and fibrosis progression.RESULTS:There were no deviations from the Hardy-Weinberg equilibrium in the human platelet antigen systems evaluated. Statistically significant differences were not observed between G1 and G2 with respect to the distributions of the allelic and genotypic frequencies of the human platelet antigen systems.CONCLUSION:The greater stimulation of hepatic stellate cells by the human immunodeficiency virus and, consequently, the increased expression of transforming growth factor beta can offset the effect of human platelet antigen polymorphism on the progression of fibrosis in patients coinfected with the human immunodeficiency virus-1 and the hepatitis C virus.

Identification of a novel determinant for membrane association in hepatitis C virus nonstructural protein 4B.

Nonstructural protein 4B (NS4B) plays an essential role in the formation of the hepatitis C virus (HCV) replication complex. It is a relatively poorly characterized integral membrane protein predicted to comprise four transmembrane segments in its central portion. Here, we describe a novel determinant for membrane association represented by amino acids (aa) 40 to 69 in the N-terminal portion of NS4B. This segment was sufficient to target and tightly anchor the green fluorescent protein to cellular membranes, as assessed by fluorescence microscopy as well as membrane extraction and flotation analyses. Circular dichroism and nuclear magnetic resonance structural analyses showed that this segment comprises an amphipathic alpha-helix extending from aa 42 to 66. Attenuated total reflection infrared spectroscopy and glycosylation acceptor site tagging revealed that this amphipathic alpha-helix has the potential to traverse the phospholipid bilayer as a transmembrane segment, likely upon oligomerization. Alanine substitution of the fully conserved aromatic residues on the hydrophobic helix side abrogated membrane association of the segment comprising aa 40 to 69 and disrupted the formation of a functional replication complex. These results provide the first atomic resolution structure of an essential membrane-associated determinant of HCV NS4B.

Hepatitis C Virus Infection and Kidney Transplantation in 2014: What's New?

Chronic hepatitis C virus (HCV) infection remains an important health problem, which is associated with deleterious consequences in kidney transplant recipients. Besides hepatic complications, several extrahepatic complications contribute to reduced patient and allograft survival in HCV-infected kidney recipients. However, HCV infection should not be considered as a contraindication for kidney transplantation because patient survival is better with transplantation than on dialysis. Treatment of HCV infection is currently interferon-alpha (IFN-α) based, which has been associated with higher renal allograft rejection rates. Therefore, antiviral treatment before transplantation is preferable. As in the nontransplant setting, IFN-free treatment regimens, because of their greater efficacy and reduced toxicity, currently represent promising and attractive therapeutic options after kidney transplantation as well. However, clinical trials will be required to closely evaluate these regimens in kidney recipients. There is also a need for prospective controlled studies to determine the optimal immunosuppressive regimens after transplantation in HCV-infected recipients. Combined kidney and liver transplantation is required in patients with advanced liver cirrhosis. However, in patients with cleared HCV infection and early cirrhosis without portal hypertension, kidney transplantation alone may be considered. There is some agreement about the use of HCV-positive donors in HCV-infected recipients, although data regarding posttransplant survival rates are controversial.

Prevalence of antibodies to Hepatitis C virus in populations at low and high risk for sexually transmited diseases in Rio de Janeiro

In order to investigate the sexual transmission of the Hepatitis C Virus (HCV), the prevalence of specific antibodies in populations at high and low risk for sexually transmitted diseases (STDs) was evaluated. The population at low risk for STDs was composed of persons who voluntarity donated blood at the Hospital Universitário Clementino Fraga Filho (HUCFF) between July and November, 1990 (n = 2494). The population at high risk for STDs was drawn from an ongoing study on the natural history of Human Immunodeficiency Virus (HIV) infection (n = 210, 187 with sexual risk factors for HIV infection). All samples were screened using a first generation ELISA. Repeat reactive samples were then tested in a second generation RIBA. For all ELISA positive samples, two sex and age-matched ELISA negative controls were selected. Data pertaining to the presence of antibodies to the Hepatitis B core antigen (anti-HBC antibodies) and to Treponema pallidum were abstracted from the medical records. The prevalence of RIBA 2 confirmed HCV infection among the blood donors was 2.08%, which is well above the reported prevalence in similar populations from developed western countries. Among the HIV infected homosexuals, the encountered prevalence was 7.96% (p < 0.0005). For the whole group with sexually acquired HIV infection, the prevalence was 8.02% (p < 0.000005). Anti-HBc antibodies were more frequently present in anti-HCV RIBA-2 confirmed positive blood donors than in controls (p < 0.001). 33.3% of the HCV-positive blood donors and 11.04% controls were found to be anti-HBc positive (p < 0.0005). As for the FTA-ABs, 17.6% HCV-positive donors and 4,9% controls were positive (p < 0.01). 5.9% samples from blood donors were both anti-HBc and FTA-ABS positive, whereas none of the controls reacted in both tests (p < 0.05). The association between HCV, Hepatitis B infection and syphilis in individuals at low risk for parenterally transmitted diseases suggests that sexual transmission contributes to the maintenance of the endemicity of HCV in the local population.

Targeting mitochondria in the infection strategy of the hepatitis C virus.

Hepatitis C virus (HCV) infection induces a state of oxidative stress more pronounced than that observed in many other inflammatory diseases. Here, we propose a temporal sequence of events in the HCV-infected cell whereby the primary alteration consists of a release of Ca(2+) from the endoplasmic reticulum, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen species and a progressive metabolic adaptive response. Evidence is provided for a positive feed-back mechanism between alterations of calcium and redox homeostasis. This likely involves deregulation of the mitochondrial permeability transition and induces progressive dysfunction of cellular bioenergetics. Pathogenetic implications of the model and new opportunities for therapeutic intervention are discussed. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.

Hepatitis C virus prevalence among an immigrant community to the Southern Amazon, Brazil

A community-based random survey was conducted in a southern Brazilian Amazonian county aiming to investigate hepatitis C virus (HCV) infection prevalence and the association of demographic variables and lifestyle behaviours. Seven hundred eighty individuals were serologically screened with a third generation enzyme-linked immunosorbent assay to detect anti-HCV antibodies between 1994/1995. Positive samples were retested for confirmation with a line immunoassay (LIA, Inno-LIA HCV Ab III). Most of these subjects were low income and came from southern Brazilian states (65.8). Two point four percent (IC 95% 1.2%- 4.6%) of the subjects had LIA-confirmed anti-HCV antibodies reactivity. The age-specific prevalence of HCV antibodies slightly increased with age, with the highest prevalence after the age of 40 years. The results of multivariate analysis indicate a strong association between HCV antibodies and previous surgery and history of intravenous drug use. There were no apparent association with gender, hepatitis B virus markers, blood transfusion, and sexual activity. Mean time living in Amazon did not differ between confirmed and negative anti-HCV individuals. The present data point out an intermediate endemicity of HCV infection among this immigrant community to the Amazon region and that few HCV infected participants presented known risk factors.

Potential exposure to hepatitis C virus through accidental blood contact in interventional radiology.

PURPOSE: To quantify the prevalence of accidental blood exposure (ABE) among interventional radiologists and contrast that with the prevalence of patients with hepatitis C virus (HCV) undergoing interventional radiology procedures. MATERIALS AND METHODS: A multicenter epidemiologic study was conducted in radiology wards in France. The risk of ABE to radiologists was assessed based on personal interviews that determined the frequency and type of ABE and the use of standard protective barriers. Patients who underwent invasive procedures underwent prospective sampling for HCV serologic analysis. HCV viremia was measured in patients who tested positive for HCV. RESULTS: Of the 77 radiologists who participated in 11 interventional radiology wards, 44% reported at least one incident of mucous membrane blood exposure and 52% reported at least one percutaneous injury since the beginning of their occupational activity. Compliance with standard precautions was poor, especially for the use of protective clothes and safety material. Overall, 91 of 944 treated patients (9.7%) tested positive for HCV during the study period, of whom 90.1% had positive viremia results, demonstrating a high potential for contamination through blood contacts. CONCLUSIONS: The probability of HCV transmission from contact with contaminated blood after percutaneous injury ranged from 0.013 to 0.030; the high frequency of accidental blood exposure and high percentage of patients with HCV could generate a risk of exposure to HCV for radiologists who perform invasive procedures with frequent blood contact. The need to reinforce compliance with standard hygiene precautions is becoming crucial for medical and technical personnel working in these wards.

Hepatitis C virus proteins promote mitochondrial bioenergetic dysfunction and nitro-oxidative stress: insights into pathogenesis

HCV-infection induces a state of oxidative stress more pronounced than in many other inflammatory diseases. Here we propose a temporal sequence of events in the HCV-infected cell whereby the primary alteration consists in release of Ca2+ from the ER followed by uptake into mitochondria. This triggers successive mitochondrial dysfunctions leading to generation of ROS and to a progressive metabolic adaptive response. Pathogenetic implications of the model and new opportunities for therapeutic intervention are discussed.

Additives and Protein-DNA Combinations Modulate the Humoral Immune Response Elicited by a Hepatitis C Virus Core-encoding Plasmid in Mice

Humoral and cellular immune responses are currently induced against hepatitis C virus (HCV) core following vaccination with core-encoding plasmids. However, the anti-core antibody response is frequently weak or transient. In this paper, we evaluated the effect of different additives and DNA-protein combinations on the anti-core antibody response. BALB/c mice were intramuscularly injected with an expression plasmid (pIDKCo), encoding a C-terminal truncated variant of the HCV core protein, alone or combined with CaCl2, PEG 6000, Freund's adjuvant, sonicated calf thymus DNA and a recombinant core protein (Co.120). Mixture of pIDKCo with PEG 6000 and Freund's adjuvant accelerated the development of the anti-core Ab response. Combination with PEG 6000 also induced a bias to IgG2a subclass predominance among anti-core antibodies. The kinetics, IgG2a/IgG1 ratio and epitope specificity of the anti-core antibody response elicited by Co.120 alone or combined with pIDKCo was different regarding that induced by the pIDKCo alone. Our data indicate that the antibody response induced following DNA immunization can be modified by formulation strategies.

Trends in drug consumption and risk of transmission of HIV and hepatitis C virus among injecting drug users in Switzerland, 1993-2006

As a part of the HIV behavioural surveillance system in Switzerland, repeated cross-sectional surveys were conducted in 1993, 1994, 1996, 2000 and 2006 among attenders of all low threshold facilities (LTFs) with needle exchange programmes and/or supervised drug consumption rooms for injection or inhalation in Switzerland. Data were collected in each LTF over five consecutive days, using a questionnaire that was partly completed by an interviewer and partly self administered. The questionnaire was structured around three topics: socio-demographic characteristics, drug consumption, health and risk/preventive behaviour. Analysis was restricted to attenders who had injected drugs during their lifetime (IDUs). Between 1993 and 2006, the median age of IDUs rose by 10 years. IDUs are severely marginalised and their social situation has improved little. The borrowing of used injection equipment (syringe or needle already used by other person) in the last six months decreased (16.5% in 1993, 8.9% in 2006) but stayed stable at around 10% over the past three surveys. Other risk behaviour, such as sharing spoons, cotton or water, was reported more frequently, although also showed a decreasing trend. The reported prevalence of HIV remained fairly stable at around 10% between 1993 and 2006; reported levels of hepatitis C virus (HCV) prevalence were high (56.4% in 2006). In conclusion, the overall decrease in the practice of injection has reduced the potential for transmission of infections. However as HCV prevalence is high this is of particular concern, as the current behaviour of IDUs indicates a potential for further spreading of the infection. Another noteworthy trend is the significant decrease in condom use in the case of paid sex.

The prevalence of human immunodeficiency virus type 1 and hepatitis C virus among injection drug users who use high risk inner-city locales in Miami, Florida

In order to estimate the prevalence of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) co-infection in hard-to-reach intravenous drug users, 199 subjects from high-risk inner-city locales, the so called "shooting galleries", were consented, interviewed, and tested in Miami, FL, US. Positive HIV-1 status was based on repeatedly reactive ELISA and confirmatory Western Blot. Positive HCV status was based on reactive ELISA and confirmatory polymerase chain reaction techniques. Overall, 50 (25%) were not infected with either virus, 61 (31%) were HIV-1/HCV co-infected, 17 (8%) infected by HIV-1 only, and 71 (36%) infected by HCV only. The results of the multivariable analyses showed that more years using heroin was the only significant risk factor for HCV only infection (odds ratio = 1.15; 95% confidence interval = 1.07, 1.24) and for HIV-1/HCV co-infection (odds ratio = 1.17; 95% confidence interval = 1.09, 1.26). This paper demonstrates that HIV-1/HCV co-infection is highly prevalent among so called "shooting galleries".