Jean-Pierre Gut

Hepatitis C Virus Envelope Glycoprotein Signatures Are Associated With Treatment Failure and Modulation of Viral Entry and Neutralization

BACKGROUND A major challenge for antiviral treatment of hepatitis C virus (HCV) infection is viral resistance, potentially resulting from the high variability of HCV envelope glycoproteins and subsequent selection of strains with enhanced infectivity and/or immune escape. METHODS We used a bioinformatics and functional approach to investigate whether E1/E2 envelope glycoprotein structure and function were associated with treatment failure in 92 patients infected with HCV genotype 1. RESULTS Bioinformatics analysis identified 1 sustain virological response (R)-related residue in E1 (219T) and 2 non-SVR (NR)-related molecular signatures in E2 (431A and 642V) in HCV genotype 1a. Two of these positions also appeared in minimal networks separating NR patients from R patients. HCV pseudoparticles (HCVpp) expressing 431A and 642V resulted in a decrease in antibody-mediated neutralization by pretreatment sera. 431A/HCVpp entry into Huh7.5 cells increased with overexpression of CD81 and SR-BI. Moreover, an association of envelope glycoprotein signatures with treatment failure was confirmed in an independent cohort (Virahep-C). CONCLUSIONS Combined in silico and functional analyses demonstrate that envelope glycoprotein signatures associated with treatment failure result in an alteration of host cell entry factor use and escape from neutralizing antibodies, suggesting that virus-host interactions during viral entry contribute to treatment failure.

Persistent multiple pulmonary nodules in a nonimmunocompromised woman after varicella-related myelitis treated with acyclovir.

ABSTRACT Persistent multiple pulmonary nodules were observed on the chest X ray of a nonimmunocompromised woman 6 months after she was treated with acyclovir for a varicella-related myelitis without respiratory symptoms. Early antiviral therapy given for varicella infections might decrease the intensity of clinical symptoms without actually preventing the occurrence of varicella-zoster virus-related lesions such as the persistent pulmonary nodules reported here.

Evidence of feline immunodeficiency virus replication in cultured Kupffer cells.

Objective: To determine if cultured feline Kupffer cells (KC) are as permissive for feline immunodeficiency virus (FIV) as cultured human liver macrophages are for HIV. Two types of infection likely to be relevant to the in vivo situation were used. KC were infected with either free virus or autologous infected peripheral blood mononuclear cells (PBMC). Methods: Feline KC were isolated by centrifugal elutriation from collagenase‐perfused liver; cultured cells were characterized by their morphological appearance and their erythrophagocytotic properties. After infection, viral replication was measured by enzyme‐linked immunosorbent assay, reverse transcriptase activity, immunofluorescence assay, in situ hybridization and electron microscopic observations. Results: Three days after isolation, 85% of cultured KC were able to internalize red blood cells; 45% were CD4‐positive and 65% expressed a 24kD protein thought to be a receptor for FIV (CD9). After the addition of autologous infected PBMC or cell‐free supernatant of chronically infected IRC4 cells to KC cultures, a peak of viral replication was detected at day 28. Antigen revealed by immunofluorescence assay was present in only 0.4%, and viral RNA was detected by in situ hybridization in 2% of the infected cells. Conclusions: FIV can replicate in cultured feline KC without inducing any cytopathic effect, which suggests that these cells may play a role in the physiopathology of FIV infection. AIDS 1995, 9:447‐453

Genotype 1 Hepatitis C Virus Envelope Features That Determine Antiviral Response Assessed through Optimal Covariance Networks

The poor response to the combined antiviral therapy of pegylated alfa-interferon and ribavarin for hepatitis C virus (HCV) infection may be linked to mutations in the viral envelope gene E1E2 (env), which can result in escape from the immune response and higher efficacy of viral entry. Mutations that result in failure of therapy most likely require compensatory mutations to achieve sufficient change in envelope structure and function. Compensatory mutations were investigated by determining positions in the E1E2 gene where amino acids (aa) covaried across groups of individuals. We assessed networks of covarying positions in E1E2 sequences that differentiated sustained virological response (SVR) from non-response (NR) in 43 genotype 1a (17 SVR), and 49 genotype 1b (25 SVR) chronically HCV-infected individuals. Binary integer programming over covariance networks was used to extract aa combinations that differed between response groups. Genotype 1a E1E2 sequences exhibited higher degrees of covariance and clustered into 3 main groups while 1b sequences exhibited no clustering. Between 5 and 9 aa pairs were required to separate SVR from NR in each genotype. aa in hypervariable region 1 were 6 times more likely than chance to occur in the optimal networks. The pair 531–626 (EI) appeared frequently in the optimal networks and was present in 6 of 9 NR in one of the 1a clusters. The most frequent pairs representing SVR were 431–481 (EE), 500–522 (QA) in 1a, and 407–434 (AQ) in 1b. Optimal networks based on covarying aa pairs in HCV envelope can indicate features that are associated with failure or success to antiviral therapy.

Primary hepatitis C virus infection in an intravenous drug user: kinetics of virological markers.

We report the follow-up of an HCV seroconversion in a 33-year-old female intravenous drug user. Successive biochemical and virological results during a one-year-follow up are listed in table I.