Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution

Abstract

The apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer.

Molecular basis of genetic variation of viruses

“…Biased hypermutation was first observed in some defective interfering (DI) RNAs of vesicular stomatitis virus (VSV) (Holland et al, 1982), and in variant forms of measles virus, associated with postmeasles neurological disease, such as subacute sclerosing panencephalitis (Cattaneo and Billeter, 1992). Hypermutation is mainly due to the activity of cellular deaminases, such as the apolipoprotein B mRNA and the editing complex (APOBEC), or the adenosine deaminase acting on doublestranded RNA (ADAR) families, that are involved in cellular editing and regulatory functions (Sheehy et al, 2002;Santiago and Greene, 2008;Nishikura, 2010;Stavrou et al, 2014;Pfaller et al, 2018;Venkatesan et al, 2018). In the event of a viral infection, such cellular functions can become part of an innate defense mechanism against the invading virus.…”

Trends in antiviral strategies

“…In Chapter 2 (Section 2.7), APOBEC (apolipoprotein B mRNA editing complex) and ADAR (adenosine deaminase acting on double-stranded RNA) were discussed. They exert nucleic acid editing functions used by the cell that can be recruited as antiviral responses (Harris and Dudley, 2015;Venkatesan et al, 2018). Editing is part of the replication cycle of several viruses.…”

Structural Investigations on the Interactions between Cytidine Deaminase Human APOBEC3G and DNA

“…APOBEC3 (A3) is known as a family of activation‐induced cytidine deaminases, including seven members APOBEC3A (A3A), APOBEC3B (A3B), APOBEC3C (A3C), APOBEC3DE (A3DE), APOBEC3F (A3F), APOBEC3G (A3G) and APOBEC3H (A3H) encoded in a tandem array on human chromosome 22 . They are characterized by the presence of one (in A3A, A3C, A3H) or two (in A3B, A3DE, A3F and A3G) conserved zinc‐coordinated domains containing HXE(X) 23–28 CXXC motifs .…”

“…They are characterized by the presence of one (in A3A, A3C, A3H) or two (in A3B, A3DE, A3F and A3G) conserved zinc‐coordinated domains containing HXE(X) 23–28 CXXC motifs . Among them, A3DE, A3F, A3G and A3H restrict replication of human immunodeficiency virus‐1 (HIV‐1) in strains lacking the virus infectivity factor protein (Vif) by deaminating cytidine in virus cDNA . Subsequent replication of the virus cDNA generates the hallmark G‐to‐A hyper‐mutations, causing proviral inactivation .…”

“…APOBEC3 (A3) is known as af amily of activation-induced cytidine deaminases, including seven members APOBEC3A (A3A), APOBEC3B (A3B), APOBEC3C (A3C), APOBEC3DE (A3DE), APO-BEC3F (A3F), APOBEC3G (A3G) and APOBEC3H (A3H) encoded in at andema rray on human chromosome2 2. [1][2][3][4] They are characterized by the presence of one (in A3A, A3C, A3H) or two (in A3B, A3DE, A3F and A3G) conserved zinc-coordinated domainsc ontaining HXE(X) [23][24][25][26][27][28] CXXC motifs. [5] Among them, A3DE, A3F,A 3G and A3H restrict replication of human immunodeficiency virus-1 (HIV-1) in strains lacking the virus infectivity factor protein (Vif) by deaminatingc ytidine in virus cDNA.…”