Host apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide-like 3G is an innate defensive factor and drug target against hepatitis C virus.

UNLABELLED: Host cellular factor apolipoprotein B messenger RNA (mRNA)-editing enzyme catalytic polypeptide-like 3G (hA3G) is a cytidine deaminase that inhibits a group of viruses including human immunodeficiency virus-1 (HIV-1). In the continuation of our research on hA3G, we found that hA3G stabilizing compounds significantly inhibited hepatitis C virus (HCV) replication. Therefore, this study investigated the role of hA3G in HCV replication. Introduction of external hA3G into HCV-infected Huh7.5 human hepatocytes inhibited HCV replication; knockdown of endogenous hA3G enhanced HCV replication. Exogenous HIV-1 virion infectivity factor (Vif) decreased intracellular hA3G and therefore enhanced HCV proliferation, suggesting that the presence of Vif might be an explanation for the HIV-1/HCV coinfection often observed in HIV-1(+) individuals. Treatment of the HCV-infected Huh7.5 cells with RN-5 or IMB-26, two known hA3G stabilizing compounds, increased intracellular hA3G and accordingly inhibited HCV replication. The compounds inhibit HCV through increasing the level of hA3G incorporated into HCV particles, but not through inhibiting HCV enzymes. However, G/A hypermutation in the HCV genome were not detected, suggesting a new antiviral mechanism of hA3G in HCV, different from that in HIV-1. Stabilization of hA3G by RN-5 was safe in vivo. CONCLUSION: hA3G appears to be a cellular restrict factor against HCV and could be a potential target for drug discovery.

Recapture of hepatic apolipoprotein B mRNA editing may be a promising strategy to relieve nephrotic dyslipidemia.

A high total plasma cholesterol concentration is the most common abnormality found in patients with kidney disease, which may be associated with the increased hepatic synthesis of apoB containing lipoproteins. ApoB mRNA editing plays an important physiological role in mammalian lipid metabolism by modifying the distribution of apoB-100 and apoB-48. However, it is regretful that apoB mRNA editing cannot be found in human liver because of the absence of apobec-1 expression. In this context, we hypothesize that the recapture of hepatic apoB mRNA editing may be a promising strategy to relieve nephrotic dyslipidemia. The data presented below focus on those which support this hypothesis with regards to evidence in vitro and in vivo. (1) Human wild-type apoB mRNA can be edited only when both apobec-1 and ACF proteins are presented simultaneously in vitro. (2) Adenoviral vectors can produce short-term expression of exogenous apobec-1 in the livers and lower plasma apoB-100 and LDL levels transiently. (3) Apobec-1 transgenic animals exhibit massive hepatic editing of apoB mRNA and fundamental decreased plasma levels of apoB-100 and LDL, but are exposed to high risk of liver dysplasia and hepatocellular carcinomas. In summary, taking into account the therapeutic security, we put forward that apobec-1 recombinant adenoviral vectors can be used for the recapture of hepatic apoB mRNA editing with a transient low-level manner and may achieve satisfactory lipid-lowing effect in nephropathic animals.

Human APOBEC3B is a potent inhibitor of HIV-1 infectivity and is resistant to HIV-1 Vif.

While the human antiretroviral defense factors APOBEC3F and APOBEC3G are potent inhibitors of the replication of HIV-1 mutants lacking a functional vif gene, the Vif protein expressed by wild-type HIV-1 blocks the function of both host cell proteins. Here, we report that a third human protein, APOBEC3B, is able to suppress the infectivity of both Vif-deficient and wild-type HIV-1 with equal efficiency. APOBEC3B, which shows approximately 58% sequence identity to both APOBEC3F and APOBEC3G, shares the ability of these other human proteins to bind the nucleocapsid domain of HIV-1 Gag specifically and to thereby package into progeny virion particles. However, APOBEC3B differs from APOBEC3F and APOBEC3G in that it is unable to bind to HIV-1 Vif in co-expressing cells and is therefore efficiently packaged into HIV-1 virions regardless of Vif expression. Unfortunately, APOBEC3B also differs from APOBEC3F and APOBEC3G in that it is not normally expressed in the lymphoid cells that serve as targets for HIV-1 infection. These studies therefore raise the possibility that activation of the endogenous APOBEC3B gene in primary human lymphoid cells could form a novel and effective strategy for inhibition of HIV-1 replication in vivo.