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.

Figure 1.

Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis within the TRACERx 100 cohort. (A) Phylogenetic trees of TRACERx patients harbouring a subclonal driver mutation in an APOBEC preferred motif are shown. The mutation is indicated near the clone in which it occurs. Clonal clusters are shown in blue, subclonal clusters are shown in red, and subclonal clusters containing the driver mutation in a preferred APOBEC motif are shown in orange. (B) The total numbers of mutations in each patient are shown, with mutations in an APOBEC context shown in orange and all other mutational contexts shown in green. (C) The total number of driver mutations in each patient are shown, with mutations in an APOBEC context shown in orange and all other mutational contexts shown in green. (D) The fraction of subclonal mutations for each patient that could be attributed to APOBEC activity are shown, with mutations in an APOBEC context shown in orange and all other mutational contexts shown in green.

Figure 2.

Parallels between APOBEC mutagenesis in HIV and cancer. (A) Within HIV, APOBEC mutagenesis is counteracted through Vif. As APOBEC mutagenesis increases, the chance of lethal mutagenesis and population variation increases. The trade-off between lethal mutagenesis and population variation creates an optimal range in which APOBEC mutagenesis increases population fitness. (B) Within cancer, the toxic effects of APOBEC mutagenesis are counteracted through DNA damage repair and DNA damage tolerance. As APOBEC mutagenesis increases, the chance of lethal mutagenesis and population variation increases. The trade-off between lethal mutagenesis and population variation creates an optimal range in which APOBEC mutagenesis increases population fitness.

Figure 3.

Potential roles of APOBEC supporting the escape and progression of HIV and cancer. (A) Sublethal APOBEC mutagenesis promotes the formation of drug escape and immune escape variants in HIV that will be selected upon exposure to treatment or the immune system. (B) Sublethal APOBEC mutagenesis promotes the formation of drug escape and immune escape variants in cancer that will be selected upon exposure to treatment or the immune system. APOBEC mutagenesis also underlies the formation of driver gene mutations and potentially also replication stress-induced genomic instability, although the latter is speculative.

Figure 4.

APOBEC mutagenesis promotes HIV immune escape and potentially also that of cancer. APOBEC mutations have been identified in cytotoxic T lymphocyte epitopes of HIV. APOBEC hypermutation has been linked to PD-L1 ligand overexpression and potentially contributes to immune exhaustion of tumour infiltrating lymphocytes. Studies within the HIV literature are suggestive of sublethal APOBEC mutagenesis driving the expansion of escape variants.

Figure 5.

A feedforward replication stress-APOBEC loop potentially drives subclonal somatic point mutations and copy number variations. APOBEC induces subclonal somatic point mutations and has recently been shown to induce replication stress. APOBEC-mediated replication stress could potentially contribute to CIN.