Sayuki Iijima

Improved capacity of a monkey-tropic HIV-1 derivative to replicate in cynomolgus monkeys with minimal modifications

Human immunodeficiency virus type 1 (HIV-1) hardly replicates in Old World monkeys. Recently, a mutant HIV-1 clone, NL-DT5R, in which a small part of gag and the entire vif gene are replaced with SIVmac239-derived ones, was shown to be able to replicate in pigtail monkeys but not in rhesus monkeys (RM). In the present study, we found that a modified monkey-tropic HIV-1 (HIV-1mt), MN4-5S, acquired the ability to replicate efficiently in cynomolgus monkeys as compared with the NL-DT5R, while neither NL-DT5R nor MN4-5S replicated in RM cells. These results suggest that multiple determinants may be involved in the restriction of HIV-1 replication in macaques, depending on the species of macaques. The new HIV-1mt clone will be useful for studying molecular mechanisms by which anti-viral host factors regulate HIV-1 replication in macaques.

Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene

Objective Recent studies have demonstrated that genetic polymorphisms near the IL28B gene are associated with the clinical outcome of pegylated interferon α (peg-IFN-α) plus ribavirin therapy for patients with chronic hepatitis C virus (HCV). However, it is unclear whether genetic variations near the IL28B gene influence hepatic interferon (IFN)-stimulated gene (ISG) induction or cellular immune responses, lead to the viral reduction during IFN treatment. Design Changes in HCV-RNA levels before therapy, at day 1 and weeks 1, 2, 4, 8 and 12 after administering peg-IFN-α plus ribavirin were measured in 54 patients infected with HCV genotype 1. Furthermore, we prepared four lines of chimeric mice having four different lots of human hepatocytes containing various single nucleotide polymorphisms (SNP) around the IL28B gene. HCV infecting chimeric mice were subcutaneously administered with peg-IFN-α for 2 weeks. Results There were significant differences in the reduction of HCV-RNA levels after peg-IFN-α plus ribavirin therapy based on the IL28B SNP rs8099917 between TT (favourable) and TG/GG (unfavourable) genotypes in patients; the first-phase viral decline slope per day and second-phase slope per week in TT genotype were significantly higher than in TG/GG genotype. On peg-IFN-α administration to chimeric mice, however, no significant difference in the median reduction of HCV-RNA levels and the induction of antiviral ISG was observed between favourable and unfavourable human hepatocyte genotypes. Conclusions As chimeric mice have the characteristic of immunodeficiency, the response to peg-IFN-α associated with the variation in IL28B alleles in chronic HCV patients would be composed of the intact immune system.

Non‐human primate surrogate model of hepatitis C virus infection

More than 170 million people worldwide are chronically infected by HCV, which is the causative agent of chronic hepatitis C, cirrhosis, and finally liver cancer. Although animal models of viral hepatitis are a prerequisite for the evaluation of antiviral and vaccine efficacy, the restricted host range of HCV has hampered the development of a suitable small animal model of HCV infection. Use of the chimpanzee, the only animal known to be susceptible to HCV infection, is limited by ethical and financial restrictions. In this regard GBV‐B, being closely related to HCV, appears to be a promising non‐human surrogate model for the study of HCV infection. This review describes the characteristic of GBV‐B infection of New World monkeys, and discusses current issues concerning the GBV‐B model and its future directions.

Genetic association of human leukocyte antigens with chronicity or resolution of hepatitis B infection in thai population.

Background Previous studies showed that single nucleotide polymorphisms (SNPs) in the HLA-DP, TCF19 and EHMT2 genes may affect the chronic hepatitis B (CHB). To predict the degree of risk for chronicity of HBV, this study determined associations with these SNPs. Methods The participants for this study were defined into 4 groups; HCC (n = 230), CHB (n = 219), resolved HBV infection (n = 113) and HBV uninfected subjects (n = 123). The HLA-DP SNPs (rs3077, rs9277378 and rs3128917), TCF19 SNP (rs1419881) and EHMT2 SNP (rs652888) were genotyped. Results Due to similar distribution of genotype frequencies in HCC and CHB, we combined these two groups (HBV carriers). The genotype distribution in HBV carriers relative to those who resolved HBV showed that rs3077 and rs9277378 were significantly associated with protective effects against CHB in minor dominant model (OR = 0.45, p<0.001 and OR = 0.47, p<0.001). The other SNPs rs3128917, rs1419881 and rs652888 were not associated with HBV carriers. Conclusions Genetic variations of rs3077 and rs9277378, but not rs3128917, rs1419881 and rs652888, were significantly associated with HBV carriers relative to resolved HBV in Thai population.

Long-term persistent GBV-B infection and development of a chronic and progressive hepatitis C-like disease in marmosets

It has been shown that infection of GB virus B (GBV-B), which is closely related to hepatitis C virus, develops acute self-resolving hepatitis in tamarins. In this study we sought to examine longitudinally the dynamics of viral and immunological status following GBV-B infection of marmosets and tamarins. Surprisingly, two of four marmosets but not tamarins experimentally challenged with GBV-B developed long-term chronic infection with fluctuated viremia, recurrent increase of alanine aminotransferase and plateaued titers of the antiviral antibodies, which was comparable to chronic hepatitis C in humans. Moreover, one of the chronically infected marmosets developed an acute exacerbation of chronic hepatitis as revealed by biochemical, histological, and immunopathological analyses. Of note, periodical analyses of the viral genomes in these marmosets indicated frequent and selective non-synonymous mutations, suggesting efficient evasion of the virus from antiviral immune pressure. These results demonstrated for the first time that GBV-B could induce chronic hepatitis C-like disease in marmosets and that the outcome of the viral infection and disease progression may depend on the differences between species and individuals.

Incidence and characteristics of HBV reactivation in hematological malignant patients in south Egypt

AIM To investigate characteristics of hepatitis B virus (HBV) implicated in HBV reactivation in patients with hematological malignancies receiving immunosuppressive therapy. METHODS Serum samples were collected from 53 patients with hematological malignancies negative for hepatitis B surface antigen (HBsAg) before the start of and throughout the chemotherapy course. HBV reactivation was diagnosed when the HBsAg status changed from negative to positive after the initiation of chemotherapy and/or when HBV DNA was detected by real-time detection polymerase chain reaction (RTD-PCR). For detecting the serological markers of HBV infection, HBsAg as well as antibodies to the core antigen (anti-HBc) and to the surface antigen were measured in the sera by CEIA. Nucleic acids were extracted from sera, and HBV DNA sequences spanning the S gene were amplified by RTD-PCR. The extracted DNA was further subjected to PCR to amplify the complete genome as well as the specific genomic sequences bearing the enhancer II/core promoter/pre-core/core regions (nt 1628-2364). Amplicons were sequenced directly. RESULTS Thirty-five (66%) of the 53 HBsAg-negative patients were found to be negative serologically for anti-HBc, and the remaining 18 (34%) patients were positive for anti-HBc. Five of the 53 (9.4%) patients with hematologic malignancies experienced HBV reactivation. Genotype D1 was detected in all five patients. Four types of mutant strains were detected in the S gene product of HBV strains and were isolated from 3 patients with HBV reactivation: T/S120, L143, and I126. HBV DNA was detected in the pretreatment HBsAg-negative samples in one of the five patients with HBV reactivation. In this patient, sequences encompassing the HBV full genome obtained from sera before the start of chemotherapy and at the time of de novo HBV hepatitis were detected and it showed 100% homology. Furthermore, in the phylogenetic tree, the sequences were clustered together, thereby indicating that this patient developed reactivation from an occult HBV infection. CONCLUSION Past infection with HBV is a risk factor for HBV reactivation in Egypt. Mandatory anti-HBc screening prior to chemotherapy in patients with hematological malignancies is recommended.

Characterization of natural killer cells in tamarins: a technical basis for studies of innate immunity.

Natural killer (NK) cells are capable of regulating viral infection without major histocompatibility complex restriction. Hepatitis C is caused by chronic infection with hepatitis C virus (HCV), and impaired activity of NK cells may contribute to the control of the disease progression, although the involvement of NK cells in vivo remains to be proven. GB virus B (GBV-B), which is genetically most closely related to HCV, induces acute and chronic hepatitis upon experimental infection of tamarins. This non-human primate model seems likely to be useful for unveiling the roles of NK cells in vivo. Here we characterized the biological phenotypes of NK cells in tamarins and found that depletion of the CD16+ subset in vivo by administration of a monoclonal antibody significantly reduced the number and activity of NK cells.

CD16+ natural killer cells play a limited role against primary dengue virus infection in tamarins

CD16 is a major molecule expressed on NK cells. To directly assess the role of natural killer (NK) cells in dengue virus (DENV) infection in vivo, CD16 antibody-treated tamarins were inoculated with a DENV-2 strain. This resulted in the transient depletion of CD16+ NK cells, whereas no significant effects on the overall levels or kinetics of plasma viral loads and antiviral antibodies were observed in the treated monkeys when compared to control monkeys. It remains elusive whether the CD16− NK subpopulation could play an important role in the control of primary DENV infection.

Serum interferon‐gamma‐inducible protein‐10 concentrations and IL28B genotype associated with responses to pegylated interferon plus ribavirin with and without telaprevir for chronic hepatitis C

Several studies have shown that high pretreatment concentrations of serum interferon‐γ‐inducible protein‐10 (IP‐10) are correlated with non‐response to pegylated interferon (PEG‐IFN) plus ribavirin (RBV) for chronic hepatitis C (CHC). However, there are few reports on their effect on the Asian population.

A Noncanonical mu-1A-Binding Motif in the N Terminus of HIV-1 Nef Determines Its Ability To Downregulate Major Histocompatibility Complex Class I in T Lymphocytes

ABSTRACT Downregulation of major histocompatibility complex class I (MHC-I) by HIV-1 Nef protein is indispensable for evasion of protective immunity by HIV-1. Though it has been suggested that the N-terminal region of Nef contributes to the function by associating with a mu-1A subunit of adaptor protein 1, the structural basis of the interaction between Nef and mu-1A remains elusive. We found that a tripartite hydrophobic motif (Trp13/Val16/Met20) in the N terminus of Nef was required for the MHC-I downregulation. Importantly, the motif functioned as a noncanonical mu-1A-binding motif for the interaction with the tyrosine motif-binding site of the mu-1A subunit. Our findings will help understanding of how HIV-1 evades the antiviral immune response by selectively redirecting the cellular protein trafficking system.