Cytidine deaminases as a weapon against retroviruses and a new target for antiviral therapy.

APOBEC3G (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G) was identified as an anti-HIV-1 (human immunodeficiency virus type 1) cellular factor in target CD4 T cells. It is a member of the APOBEC family of cytidine deaminases consisting of APOBEC1, APOBEC2, APOBEC3 (A to H), and AID (activation induced deaminase). During reverse transcription, it deaminates dC to dU in nascent minus-strand viral DNA, resulting in G-to-A hypermutation in the plus strand DNA to inhibit the replication of HIV-1. On the contrary, HIV-1 Vif protein counteracts this enzyme by the ubiquitin-proteasome pathway to enable HIV-1 replicate in target cells. Vif forms an E3 ligase complex with cellular proteins including Cullin5, ElonginB, and ElonginC (Vif-BC-Cul5) and functions as a substrate recognition subunit of the complex to target APOBEC3G for ubiquitin-proteasome dependent degradation in virus-producing cells. APOBEC3G has also been shown to have a broad antiviral activity on a wide variety of viruses which include not only retroviruses such as other lentiviruses, murine leukemia virus (MLV), and human T-cell leukemia virus type 1 (HTLV-1) but also other viruses such as hepatitis B virus (HBV) and adeno-associated virus. Furthermore, other members of the APOBEC family also show a broad antiviral activity, but target virus specificities vary among APOBEC members. On the other hand, viruses have their own mechanisms to escape from APOBEC. These expanding evidences suggest that the APOBEC family of cytidine deaminases plays an important role in antiviral innate immunity and might be a novel target for an antiviral therapy. Here we review the present understanding of APOBEC3 proteins as an antiviral innate immunity and battles between APOBEC3 and viruses.