Comparative Analysis of Nonstructural Proteins NS3 and NS5A of Hepatitis C Virus Obtained from patients with and witout Hepatocellular Carcinoma

兵庫県及び山形県から得られた検体を用いて, 原発性肝細胞癌 (HCC) 患者及び非癌患者のC型肝炎ウイルス (HCV) の非構造タンパク質NS3とNS5Aの変異について比較解析し, HCC発症におけるこれらの変異の意義を検討した。NS3のアミノ末端領域のアミノ酸配列にはかなりの多様性がみられ, HCV-1b株はその二次構造によってグループAとグループBの2群に大別された。兵庫県, 山形県いずれにおいても, 非癌患者由来株では約半数がグループAであり, 残りはグループBあるいはそれに類似する変異株であった。一方, HCC患者由来株では, グループAは10～20%のみで, 残りの80～90%はグループBあるいはそれに類似する変異株であった。これらのことから, グループAは低発癌性ウイルス株, グループBは高発癌性ウイルス株である可能性が示唆された。NS5Aについては, 兵庫県, 山形県ともに, HCC患者由来株では, 非癌患者由来株に比べて, インターフェロン感受性決定領域 (ISDR) に4ケ所以上のアミノ酸変異を有するものが多くみられた。以上の成績は, NS3アミノ末端領域の二次構造解析によって高発癌性ウイルス株を同定し, HCC発症危険性を予測し得る可能を示すとともに, 高発癌性ウイルス株の多くはインターフェロン感受性であり, HCC発症予防にインターフェロンが有効であることの理論的根拠を示すものである。 / The nonstructural proteins 3 and 5A (NS3 and NS5A, respectively) of hepatitis C virus subtype 1b (HCV-1b) obtained from patients with and without hepatocellular carcinoma (HCC) in Hyogo and Yamagata Prefectures were analyzed to see any possible correlation between mutations of the viral proteins and development of HCC. A considerable degree of variation was observed with the amino acid sequence of an amino-terminal portion of NS3. On the basis of secondary structure of amino-terminal 180 residues of NS3, HCV-1b isolates were classified into two major groups; group A and group B. In both Hyogo and Yamagata Prefectures, about half of the HCV-1b isolates from patients without HCC belonged to group A while the remaining half belonged to group B and a group B-like variant group. On the other hand, 80-90% of the isolates from patients with HCC belonged to group B and the variant group. The distribution patterns of those groups were significantly different between patients with HCC and those without HCC (P<0.001). Thus, group B isolates were highly associated with HCC and this secondary structure analysis would be useful to predict high risk for development of HCC in HCV-1b-infected patients. As for NS5A, HCV-1b isolates obtained from patients with HCC showed more mutations in interferon (IFN) sensitivity-determining region (ISDR). This result suggests the possibility that HCV-1b isolates that are highly associated with HCC are more sensitive to IFN treatment, claiming the effectiveness of IFN to prevent development of HCC

Vaccination against Heterologous R5 Clade C SHIV: Prevention of Infection and Correlates of Protection

A safe, efficacious vaccine is required to stop the AIDS pandemic. Disappointing results from the STEP trial implied a need to include humoral anti-HIV-1 responses, a notion supported by RV144 trial data even though correlates of protection are unknown. We vaccinated rhesus macaques with recombinant simian immunodeficiency virus (SIV) Gag-Pol particles, HIV-1 Tat and trimeric clade C (HIV-C) gp160, which induced cross-neutralizing antibodies (nAbs) and robust cellular immune responses. After five low-dose mucosal challenges with a simian-human immunodeficiency virus (SHIV) that encoded a heterologous R5 HIV-C envelope (22.1% divergence from the gp160 immunogen), 94% of controls became viremic, whereas one third of vaccinees remained virus-free. Upon high-dose SHIV rechallenge, all controls became infected, whereas some vaccinees remained aviremic. Peak viremia was inversely correlated with both cellular immunity (p<0.001) and cross-nAb titers (p<0.001). These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time

Comparative Analysis of Nonstructural Proteins NS3 and NS5A of Hepatitis C Virus Obtained from Patients with and without Hepatocellular Carcinoma

博士（医学）神戸大