Retroviral restriction by APOBEC proteins

Abstract

A powerful mechanism of vertebrate innate immunity has been discovered in the past year, in which APOBEC proteins inhibit retroviruses by deaminating cytosine residues in nascent retroviral cDNA. To thwart this cellular defence, HIV encodes Vif, a small protein that mediates APOBEC degradation. Therefore, the balance between APOBECs and Vif might be a crucial determinant of the outcome of retroviral infection. Vertebrates have up to 11 different APOBEC proteins, with primates having the most. APOBEC proteins include AID, a probable DNA mutator that is responsible for immunoglobulin-gene diversification, and APOBEC1, an RNA editor with antiretroviral activities. This APOBEC abundance might help to tip the balance in favour of cellular defences.

APOBEC3 genes: retroviral restriction factors to cancer drivers

“…The human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) gene family comprises 11 genes: the Activation-Induced Cytidine Deaminase (AICDA), APOBEC1 (A1) and seven A3s encode (deoxy)cytidine deaminases capable of targeting RNA and/or DNA; A2 does not appear to posses catalytic activity and A4 remains uncharacterized [1]. The founding member, A1 was cloned over 20 years ago and shown to be responsible for the deamination (see Glossary) of cytidine 6666 in the ApoB mRNA, converting it to uridine and generating a stop codon that creates a shorter ApoB 48 protein [2,3].…”

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

“…24 APOBEC3 proteins constitute a powerful mechanism of vertebrate innate immunity by providing intracellular resistance to retrovirus replication. 25 Human APOBEC3A has the ability to enter the nucleus and shows specificity for singlestranded DNA. The inhibition of AAV by hA3A is the first example of an APOBEC protein that targets a virus that replicates exclusively in the nucleus without passing through an RNA intermediate.…”

Intracellular trafficking of retroviral vectors: obstacles and advances

“…These classes of restriction factors are considered below but more detailed reviews are found elsewhere. 30,[73][74][75] Interferons are also well established to perturb early retroviral infection, lowering proviral DNA, [76][77][78][79] but are not discussed here due to space constraints.…”

“…80 Since this seminal study, multiple human APOBEC3 family members and their homologues in other species are reported to block diverse retroviruses (reviewed in Harris and Liddament 75 ). The APOBEC3 proteins belong to an enzyme family that all deaminate cytidine (C) bases to uracil (U) in DNA or RNA.…”

“…83 To function, human APOBEC3G is packaged into virions in producer cells but blocks viral replication in target cells (discussed in Harris and Liddament 75 ), most likely by degrading the viral cDNA between late reverse transcription and integration. 84 In defense, the lentiviruses use their viral infectivity factor (Vif) accessory protein to prevent APOBEC3 packaging into virions in producer cells and circumvent restriction in target cells (reviewed in Anderson and Hope 30 and Harris and Liddament 75 ). Importantly, as APOBEC3 must be present in the virus-producing cell for packaging into virions and then restriction in target cells, this negative role of APOBEC3 can be readily eliminated from retroviral gene therapy vectors by producing virions in cells lacking APOBEC3.…”