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Biomedical subjects

Jacques Izopet

Publications and source records attributed to Jacques Izopet.

At least 19 recordsLinked to original sources
PubMed2026

Host-interferon-stimulated gene response to virus-host recombinant variants of hepatitis E virus and enhanced viral replication.

The hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. HEV infection can become chronic in immunocompromised individuals, in whom virus-host recombinant variants (VHRVs) can be detected. These variants often harbor host-derived insertions in the polyproline-rich region (PPR), and most display enhanced replication in vitro. However, the mechanisms underlying this replicative advantage remain unclear. It is likely that genes of the infected cells are differentially expressed according to the replicative capacity of the strain. The host factors involved in the improvement of the replicative capacity of these VHRVs are yet to be identified.In this study, we analyzed the host transcriptional response to seven VHRVs in HepG2/C3A cells using bulk RNA sequencing at 48 h and 168 h post-infection. Five VHRVs (RNF19A, ZNF787, KIF1B, RPS17, EEF1A1) previously associated with a high replication rate induced more significant, distinct transcriptomic changes than low-replicative variants (RNA18, RPL6), particularly at 168 h. A shared set of 25 genes, especially interferon-stimulated genes (ISGs), was upregulated in cells infected with high-replicating variants. Interestingly, ISG induction was limited at 48 h despite high viral RNA concentrations, suggesting a delayed antiviral response. At 168 h, high ISG expression coincided with high viral loads, indicating that VHRVs may evade or exploit immune defenses. Our findings reveal candidate ISGs such as IFIT1 and ISG15 that may influence HEV persistence and immune escape. These results offer new insights into the interplay between VHRV replication and host immunity.IMPORTANCEHepatitis E virus (HEV) is a major cause of acute hepatitis and can cause chronic infections in immunocompromised individuals. Virus-host recombinant variants (VHRVs) having integrated host-derived insertions often replicate more effectively, yet the host determinants of this phenotype remain unclear. With RNA sequencing of HepG2/C3A-infected cells, we observed that high-replicating VHRVs induce a delayed but strong expression of interferon-stimulated genes (ISGs), including IFIT1 and ISG15, despite high viral loads. These results suggest that VHRVs may transiently modulate or evade aspects of host antiviral defenses. Our study revealed host transcriptional patterns associated with enhanced viral replication, providing insight into potential mechanisms that enhance HEV replication and highlighting candidate pathways that could influence the interplay between viral replication and immune responses, all requiring further investigation.

Humans↗
PubMed2007

Genetic diversity of HCV genotype 2 strains in south western France.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver disease worldwide. The genetic heterogeneity of HCV and its spread among infected patients can be examined accurately by nucleotide sequencing. The diversity of HCV genotype 2 strains (HCV-2) was studied in a large cohort of patients in the Midi Pyrénées area of southern France. Phylogenetic analysis was performed on 344 NS5B sequences from patients infected with HCV-2. These included 145 strains whose E2 region was also analyzed, and epidemiological data were collected for the corresponding patients. HCV-2 accounts for 11.3% of HCV infections in this area. Phylogenetic analysis of NS5B sequences revealed eight subtypes, while that of the E2 region provided congruent results for 100% of strains. The most frequent subtypes were 2i (24.7%), 2k (22.4%) 2c (17.4%), and 2a (10.8%). The mean age of HCV-2-infected patients was 55.5 years. Epidemiological data showed that blood transfusion is the major route of infection, but it was not associated with any particular subtype. By contrast, intravenous drug users were infected predominantly with genotype 2a. HCV-2a-infected patients were younger than patients infected with other subtypes (48 vs. 56.5 years, P < 0.01). This study shows substantial genetic diversity of HCV-2 subtypes in the south of France and the spread of 2a strains via intravenous drug users.

Cohort Studies↗
PubMed2006

Treatment of hepatitis C virus infection (HCV) after renal transplantation: implications for HCV-positive dialysis patients awaiting a kidney transplant.

Patient survival is significantly lower in hepatitis C virus (HCV)-positive compared to HCV-negative dialysis patients. After renal transplantation, immunosuppressive therapy can result in an increased burden of HCV viremia. Both patient and graft survivals are lower in HCV-positive compared to matched HCV-negative renal-transplant patients. Therefore, it is important to treat HCV infection. At present, after renal transplantation, there is no current safe and efficient therapy. Alpha-interferon (alpha-IFN) does not give a sustained virological response, and is associated with a high rate of renal failure. Ribavirin and amantadine monotherapies are associated with a significant improvement in liver enzymes, but have no impact upon HCV viremia. Ribavirin, however, may be indicated in cases of HCV-related glomerulopathy because it can significantly decrease proteinuria. The combined use of alpha-IFN and ribavirin should only be given to those patients who have developed posttransplant fibrosing cholestatic hepatitis. Therefore, HCV infection needs to be treated pretransplant. In dialysis patients, the only recommended therapy, as yet, is alpha-IFN monotherapy. Pegylated alpha-IFN is under evaluation and ribavirin is contraindicated because it results in severe hemolytic anemia. Twelve months of alpha-IFN therapy results in sustained virological clearance in approximately 40% of patients, regardless of their genotype. HCV RNA, after three months of alpha-IFN therapy, is a predictive factor for a long-term sustained response. Finally, when HCV-positive dialysis patients with a sustained virological response undergo successful renal transplantation, very few suffer a virological relapse, thus emphasizing that these patients were cured.

Antiviral Agents↗
PubMed2006

Validation of an automated real-time PCR protocol for detection and quantitation of HIV and HCV genomes in semen.

The ability to detect and quantify HIV and HCV genomes is important for checking spermatozoid preparation protocols also known as "sperm washing". But no commercial assay is available. A method was developed for detecting HIV and HCV in semen fractions using the COBAS Ampliprep and COBAS Taqman instruments. It will detect fewer than 200 copies of HIV RNA per ml of semen plasma and fewer than 200 copies/3 x 10(6) semen cells. The sensitivity for HCV is similar at more than 200 IU/ml and below 200 IU/3 x 10(6) semen cells. No inhibitor of PCR amplification was detected. This automated protocol permits a convenient, standardized testing for HIV and HCV in semen. The performance is the same as that of the previous generation of automated assays but the cost and operating time are both reduced.

Genome, Viral↗
PubMed2006

Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment.

BACKGROUND: The recording of outcomes from large-scale, simplified HAART (highly active antiretroviral therapy) programmes in sub-Saharan Africa is critical. We aimed to assess the effectiveness of such a programme held by Médecins Sans Frontières (MSF) in the Chiradzulu district, Malawi. METHODS: We scaled up and simplified HAART in this programme since August, 2002. We analysed survival indicators, CD4 count evolution, virological response, and adherence to treatment. We included adults who all started HAART 6 months or more before the analysis. HIV-1 RNA plasma viral load and self-reported adherence were assessed on a subsample of patients, and antiretroviral resistance mutations were analysed in plasma with viral loads greater than 1000 copies per mL. Analysis was by intention to treat. FINDINGS: Of the 1308 patients who were eligible, 827 (64%) were female, the median age was 34.9 years (IQR 29.9-41.0), and 1023 (78%) received d4T/3TC/NVP (stavudine, lamivudine, and nevirapine) as a fixed-dose combination. At baseline, 1266 individuals (97%) were HAART-naive, 357 (27%) were at WHO stage IV, 311 (33%) had a body-mass index of less than 18.5 kg/m2, and 208 (21%) had a CD4 count lower than 50 cells per muL. At follow-up (median 8.3 months, IQR 5.5-13.1), 967 (74%) were still on HAART, 243 (19%) had died, 91 (7%) were lost to follow-up, and seven (0.5%) discontinued treatment. Low body-mass index, WHO stage IV, male sex, and baseline CD4 count lower than 50 cells per muL were independent determinants of death in the first 6 months. At 12 months, the probability of individuals still in care was 0.76 (95% CI 0.73-0.78) and the median CD4 gain was 165 (IQR 67-259) cells per muL. In the cross-sectional survey (n=398), 334 (84%) had a viral load of less than 400 copies per mL. Of several indicators measuring adherence, self-reported poor adherence (<80%) in the past 4 days was the best predictor of detectable viral load (odds ratio 5.4, 95% CI 1.9-15.6). INTERPRETATION: These data show that large numbers of people can rapidly benefit from antiretroviral therapy in rural resource-poor settings and strongly supports the implementation of such large-scale simplified programmes in Africa.

Adult↗
PubMed2006

Repeated HIV-1 resistance genotyping external quality assessments improve virology laboratory performance.

The performance of French virology laboratories belonging to the ANRS network has been assessed annually for 3 years. The performance of these laboratories was compared between the years 2002 and 2003. Ten and 7 coded samples were sent to 38 virology laboratories in 2002 and 45 virology laboratories in 2003, respectively. Each panel of coded samples included at least one HIV-negative control, a pair of duplicate specimens, samples with a wide range of viral loads, and samples with a large number of resistance mutations. The laboratories used their standard sequencing procedures and were asked to report the amino acids at codons associated with resistance mutations, based on the IAS-USA expert panel list. The reference amino acid sequences were defined as those most frequently reported by the participants. The specificity of detection of RT mutations was significantly better in 2003 (99.9%) than in 2002 (99.7%) (P = 0.05). There was no difference between 2002 and 2003 in the specificity of detection of protease mutations (99.6% and 99.8%) or the sensitivity of detection of RT mutations (98.8% and 98.2%). The sensitivity of detection of protease mutations improved significantly between 2002 and 2003 (97.6% and 99.0%, respectively; P = 0.037). The proportion of laboratories reporting fully accurate results, in terms of amplification, specificity, sensitivity, and reproducibility, tended to increase between 2002 and 2003 (P = 0.077). No errors were made by 19% of laboratories in 2002, compared to 42% in 2003. These results show the value of repeated external quality assessments.

Clinical Laboratory Techniques↗
PubMed2006

Hepatitis C virus infection among dialysis patients in Tunisia: incidence and molecular evidence for nosocomial transmission.

In order to study the incidence of hepatitis C virus (HCV) infection in Tunisian haemodialysis patients and detect its nosocomial transmission, 395 patients were enrolled in a prospective study (November 2001-2003). HCV serological and virological status was determined initially using, respectively a third generation ELISA and an RT-PCR qualitative assay. The genotype of the HCV isolates was determined by sequencing NS5B region. The issue of nosocomial transmission was addressed by sequencing the HVR-1 region of the E2 gene. About 20% of the patients had anti-HCV antibodies and HCV-RNA was detected in 73% of the anti-HCV positive patients. Two cases of de novo HCV infection were identified in two dialysis centers, during virological follow-up of patients susceptible to HCV infection. The incidence of de novo HCV infection was 0.5%. Determining the genotypes in the first center disclosed that all HCV-positive patients were infected with genotype 1b; sequencing of the HVR-1 region of the E2 gene provided strong evidence that the isolate from the newly infected patient and another infected dialysis patient were closely related, confirming nosocomial contamination. The investigation of the second center is pending. Besides, one patient with negative HCV serology had detectable HCV-RNA at the beginning of the study. This case had HCV genotype 1b, two other infected dialysis patients in the same unit had HCV genotypes 4k and 3a; thus precluding nosocomial transmission. Thanks to molecular and phylogenetic methods, one case of nosocomial HCV transmission in haemodialysis was confirmed. Epidemiological investigation suggested nosocomial transmission via the medical and/or nursing staff.

Adolescent↗
PubMed2006

Twenty-four hour kinetics of hepatitis C virus and antiviral effect of alpha-interferon.

Numerous studies reported that patients infected by the genotype 1 of hepatitis C virus (HCV) and/or with a high baseline viral load responded poorly to antiviral therapy. Study of viral kinetics has provided clues to the understanding of non-response to alpha-interferon (IFN-alpha)-based therapy. The objective of this study was to clarify the influence of viral factors such as the genotype and baseline viral load on HCV resistance to treatment through the study of their impact on the first phase of viral decline. HCV RNA levels were determined frequently following the administration of 3 million units of IFN-alpha in 22 chronic HCV carriers. The evolution of HCV RNA level over 24 hr was different in genotype 1-infected patients, compared to that in patients infected by other genotypes. The viral load decline at 24 hr was lower in patients with genotype 1. Patients with a high baseline viral load exhibited a viral dynamics different from patients with a lower level of viremia; the extent of the first phase was also lower in these patients. Non-responder patients had a slower viral decay on day 1 of therapy than patients who cleared the virus under treatment. In conclusion, 24 hr HCV dynamics is regulated by genotype and baseline viral load. Genotype 1 strains and those that produce high viral loads are the most resistant to the antiviral action of IFN-alpha. Resistant HCV strains could be distinguished from sensitive viruses as early as a few hours after the beginning of the treatment.

Adult↗
PubMed2006

Hepatitis E is an autochthonous disease in industrialized countries. Analysis of 23 patients in South-West France over a 13-month period and comparison with hepatitis A.

OBJECTIVES: Hepatitis E virus (HEV) is responsible for acute hepatitis predominantly in developing countries. In Western Europe and in the US, cases of acute HEV infection are uncommon and occur primarily in travelers returning from endemic countries. The aim of this study was to describe patients with acute hepatitis E in South West France and compare them with patients with acute hepatitis A. METHODS: 23 consecutive patients over 13 months were analysed. Acute hepatitis E was diagnosed on the presence of specific serum antibodies or viral RNA detection in serum or stools. Real time PCR products from viraemic patients were sequenced. RESULTS: All the HEV sequences belonged to genotype 3. Two patients (8%) died during their hospital stay, both suffered from severe underlying disease. Only 3 patients (13%) had travelled outside of Europe, within 3 months of the onset of disease. When compared to 23 patients with acute hepatitis A at the same hospital and during the same time frame, HEV-infected patients were older (54.4 +/- 16.6 vs 24.5 +/- 16.6, P<0.05), had lower ALT levels (55.4 X upper normal limit +/- 48.6 vs 107.8 X upper normal limit +/- 82.8, P<0.05) and had lower incidence of recent travel outside of Europe (13% in the hepatitis E group vs 60% in the hepatitis A group, P<0.05). CONCLUSIONS: Hepatitis E can be considered an autochthonous infection in South West France. All strains sequenced were related to genotype III. When compared to hepatitis A, HEV-infected patients were older, had lower ALT levels and had a lower incidence of travel outside of Europe.

Adult↗
PubMed2006

Analysis of CCR5, CCR2, CX3CR1, and SDF1 polymorphisms in HIV-positive treated patients: impact on response to HAART and on peripheral T lymphocyte counts.

Although polymorphisms of chemokine genes (SDF1, stromal cell-derived factor-1 and RANTES, regulated on activation, normal T cell expressed and secreted) and chemokine-receptor genes (CCR5, CCR2, CX(3)CR1) were shown to be associated with sensitivity to HIV infection and untreated HIV disease progression, their association with the response to highly active antiretroviral therapy (HAART) remains unclear. To explore the possible influence of such polymorphisms on the evolution of AIDS in treated patients, we have studied SDF1-3'A, CCR5Delta32, CCR2-64I, CX(3)CR1-249I, and CX(3)CR1-280M polymorphisms in HIV-infected patients under HAART (n = 169). We studied the evolution of plasma virus load and peripheral T lymphocyte counts in these patients up to 3 years after the initiation of HAART. We observed that some of the genetic polymorphisms studied had an impact on the evolution of these two parameters. After 1 year of HAART, patients with a virological response (undetectable plasma HIV-1 RNA) have a higher frequency of the homozygous SDF1-3'A genotype than other patients (p = 0.005). Similarly, patients with a CD4 increase of over 200/mm(3) from baseline after 1 year of HAART display higher frequencies of homozygous SDF1-3'A (p = 0.035) and homozygous CX(3)CR1-280M genotypes (p = 0.04) than other patients. Moreover, we showed that the CX(3)CR1- 280M allele was associated with higher peripheral CD4+ T cell counts not only in HIV+ patients but also in healthy controls (p = 0.003).

Adult↗
PubMed2006

Unique NS5b hepatitis C virus gene sequence consensus database is essential for standardization of genotype determinations in multicenter epidemiological studies.

A multicenter study of NS5b hepatitis C virus (HCV) genotype determination involving 12 laboratories demonstrates that any laboratory with expertise in sequencing techniques would be able to provide a reliable HCV genotype for clinical and epidemiological purposes as long as they are provided a consensus reference sequence database.

Consensus Sequence↗
PubMed2006

Naive T-cell depletion related to infection by X4 human immunodeficiency virus type 1 in poor immunological responders to highly active antiretroviral therapy.

The reasons for poor CD4+ T-cell recovery in some human immunodeficiency virus (HIV)-infected subjects despite effective highly active antiretroviral therapy (HAART) remain unclear. We recently reported that CXCR4-using (X4) HIV-1 could be gradually selected in cellular reservoirs during sustained HAART. Because of the differential expression of HIV-1 coreceptors CCR5 and CXCR4 on distinct T-cell subsets, the residual replication of R5 and X4 viruses could have different impacts on T-cell homeostasis during immune reconstitution on HAART. We examined this hypothesis and the mechanisms of CD4+ T-cell restoration by comparing the virological and immunological features of 15 poor and 15 good immunological responders to HAART. We found a high frequency of X4 viruses in the poor immunological responders. But the levels of intrathymic proliferation of the two groups were similar regardless of whether they were infected by R5 or X4 virus. The frequency of recent thymic emigrants in the poor immunological responders was also similar to that found in the good immunological responders, despite their reduced numbers of naïve CD4+ T cells. Our data, rather, suggest that the naïve T-cell compartment is drained by a high rate of mature naïve cell loss in the periphery due to bystander apoptosis or activation-induced differentiation. X4 viruses could play a role in the depletion of naïve T cells in poor immunological responders to HAART by triggering persistent T-cell activation and bystander apoptosis via gp120-CXCR4 interactions.

Adult↗
PubMed2005

[The evolution of the hypervariable region-1 of hepatitis C virus may predict liver fibrosis outcome after renal transplantation].

The aim of our study was to assess hepatitis C virus (HCV) evolution and long term liver histology outcome in anti-HCV(+)/RNA(+) renal-transplant (RT) patients. Fifty-five anti-HCV(+)/RNA(+) RT patients underwent every 3-4 years after transplantation liver biopsies (LB) (2 LBs, N = 55; 3 LBs, N = 44; 4 LBs, N = 10). The hypervariable region (HVR)-1 of the HCV genome from all patients was characterized over time. Overall, the rate of liver fibrosis progression was 0.07 +/- 0.03 Metavir units/year. We identified three groups of patients: those in whom liver fibrosis remained stable (group I, N = 21), those with progressing liver fibrosis (group II, N = 21), and those with a regression in liver fibrosis (group III, N = 13). Initial fibrosis stage and high diversification of the HVR-1 of HCV genome between the transplantation and the first liver biopsy were independent factors associated with liver fibrosis regression. In conclusion, in this study, after renal transplantation, HCV infection is not harmful upon liver histology in more than fifty percent of the patients. The diversification of the HVR-1 of the HCV genome might be used to predict liver fibrosis outcome.

Adult↗
PubMed2005

Persistence of distinct HIV-1 populations in blood monocytes and naive and memory CD4 T cells during prolonged suppressive HAART.

OBJECTIVE: Reservoirs of HIV-1 are a major obstacle to virus eradication. There is therefore a need to clearly understand the molecular nature of the virus populations that persist in patients with sustained suppression of plasma viraemia on highly active antiretroviral therapy (HAART). DESIGN: We performed a detailed analysis of the genotypes of HIV-1 quasispecies isolated from highly purified blood cell types taken from three selected patients with sustained undetectable viral loads on HAART for 7 years. METHODS: We used polychromatic flow cytometry to sort naive and memory CD4 T cells, CD14 monocytes, and CD56+CD3- natural killer (NK) cells from the total peripheral blood mononuclear cells after 7 years of HAART. Clonal analysis was used to determine coreceptor use and drug-resistance genotypes of HIV-1 quasispecies in the sorted blood cell types. RESULTS: We detected HIV-1 DNA in memory and naive CD4 T cells and in CD14 monocytes, but not in the CD56+CD3- NK cells. Phylogenetic analysis demonstrated that the various blood cells types of two of the three patients harboured genetically distinct HIV-1 quasispecies. Drug-resistance mutations were also distributed differently from one cell type to another. This compartmentalization suggests a minimal virus trafficking between blood cell types during suppressive HAART. CONCLUSIONS: We observed a cell-specific compartmentalization of the residual virus populations during prolonged suppressive HAART. The coexistence of numerous HIV-1 quasispecies with different resistance genotypes and coreceptor use in cellular reservoirs may be relevant for future antiretroviral treatment strategies.

Antiretroviral Therapy, Highly Active↗
PubMed2005

French national sentinel survey of antiretroviral drug resistance in patients with HIV-1 primary infection and in antiretroviral-naive chronically infected patients in 2001-2002.

OBJECTIVE: To survey the frequency of genotypic antiretroviral resistance and the spread of non-B subtypes in patients with primary HIV-1 infection (2001-2002) and in treatment-naive chronically HIV-1-infected patients (2001). METHODS: Plasma samples from 303 patients with acute HIV-1 infection (Primo study) and 363 treatment-naive patients with chronic HIV-1 infection (Odyssee study) were tested for genotypic resistance. Resistance mutations were identified from the International AIDS Society Resistance Testing-USA panel and resistant viruses were defined according to the French Agence Nationale de Recherches sur le SIDA (ANRS) resistance algorithm. RESULTS: In the Primo study, 14% of the patients had viruses with resistance mutations and 12% of patients had viruses with mutations conferring resistance to least 1 antiretroviral drug. Thirty patients had viruses with mutations to at least 1 antiretroviral drug in a single pharmacologic class. Six patients were infected by viruses resistant to 2 or 3 classes of drugs. In the Odyssee study, the prevalence of reverse transcript (RT) associated and major protease inhibitor-associated mutations was 6.1% (95% CI: 3.6-8.6). Six patients had viruses resistant to at least 1 antiretroviral drug and 3 patients had viruses resistant to 2 classes of antiretroviral drugs. Twenty-four percent of acutely infected patients harbored non-B subtype strains (19% in 1999-2000) and 33.2% of chronically infected patients (10% in 1998; P < 0.0001). CONCLUSION: In France, the frequency of HIV-1 resistance in untreated patients was not significantly higher in 2001-2002 than in previous surveys while the prevalence of non-B subtypes is increasing.

Acquired Immunodeficiency Syndrome↗
PubMed2005

R5 to X4 switch of the predominant HIV-1 population in cellular reservoirs during effective highly active antiretroviral therapy.

HIV-1 coreceptor usage plays a critical role for virus tropism and pathogenesis. A switch from CCR5 to CXCR4-using viruses can occur in the natural course of infection and correlates with subsequent disease progression. To investigate whether HIV-1 genetic evolution might lead to changes in virus coreceptor usage during highly active antiretroviral therapy (HAART), a longitudinal genotypic analysis of the virus found in cellular reservoirs was conducted in 32 patients with undetectable viral loads on HAART for 5 years. The genotype of the 3rd variable region of the env gene predicting coreceptor usage was retrospectively determined in the plasma or in peripheral blood mononuclear cells (PBMC) at baseline and then in PBMCs at months 30 and 60 of HAART. There was a switch from R5 to X4 variants in 11 of the 23 patients who harbored a majority virus population of R5 variants at baseline. X4 variants remained predominant in the 9 patients who harbored mainly X4 variants at baseline. The patients harboring predominantly X4 variants during HAART, either from baseline or after an R5 to X4 switch, tended to have lower CD4+ T-cell counts on HAART than did patients harboring continuously a majority population of R5 variants. These results suggest that potent antiretroviral therapy produces the conditions necessary for the gradual emergence of X4 variants in cellular reservoirs.

Acquired Immunodeficiency Syndrome↗