APOBEC3 Proteins in Viral Immunity

Abstract

Apolipoprotein B editing complex 3 family members are cytidine deaminases that play important roles in intrinsic responses to infection by retroviruses and have been implicated in the control of other viruses, such as parvoviruses, herpesviruses, papillomaviruses, hepatitis B virus, and retrotransposons. Although their direct effect on modification of viral DNA has been clearly demonstrated, whether they play additional roles in innate and adaptive immunity to viruses is less clear. We review the data regarding the various steps in the innate and adaptive immune response to virus infection in which apolipoprotein B editing complex 3 proteins have been implicated.

Figure 1

Role of APOBEC3 proteins in anti-viral immunity. APOBEC3 proteins are ISGs, whose expression is induced by IFNs and other chemokines/cytokines produced by cells in response to infection. APOBEC3 molecules are either packaged into virions or produced by the target cell, leading to deamination of cytosine residues in viral reverse-transcribed DNA; this leads to the generation of stop codons, in the case of A3G (red molecule) or missense mutations with the other A3 proteins (blue molecule). Certain cells, such as B cells, may also shed APOBEC3 in exosomes, which can be transmitted to virus-infected cells and either be packaged into viruses (A) or deaminate viral reverse transcripts which then integrate into the genome. These cells, as well as cells directly infected with virions containing packaged A3 (B), produce dead or attenuated viruses. When APCs are infected (C), the introduction of mutations generates truncated or misfolded proteins, which are degraded by the proteasome and provide MHC-I epitopes leading to increased CTL responses and destruction of infected cells. In other cells (D), U residues in DNA generated by APOBEC3-mediated deamination are cleaved by UNG2, generating gaps that are acted upon by the cell’s base excision repair (BER) machinery, triggering a DNA damage response (DDR). This in turn induces increases NK ligand expression and NK-mediated killing of infected cells.