Viral subversion of APOBEC3s: Lessons for anti-tumor immunity and tumor immunotherapy

Abstract

APOBEC3s (A3) are endogenous DNA-editing enzymes that are expressed in immune cells including T lymphocytes. A3s target and mutate the genomes of retroviruses that infect immune tissues such as the human immunodeficiency virus (HIV). Therefore, A3s were classically defined as host anti-viral innate immune factors. In contrast, we and others showed that A3s can also benefit the virus by mediating escape from adaptive immune recognition and drugs. Crucially, whether A3-mediated mutations help or hinder HIV, is not up to chance. Rather, the virus has evolved multiple mechanisms to actively and maximally subvert A3 activity. More recently, extensive A3 mutational footprints in tumor genomes have been observed in many different cancers. This suggests a role for A3s in cancer initiation and progression. On the other hand, multiple anti-tumor activities of A3s have also come to light, including impact on immune checkpoint molecules and possible generation of tumor neo-antigens. Here, we review the studies that reshaped the view of A3s from anti-viral innate immune agents to host factors exploited by HIV to escape from immune recognition. Viruses and tumors share many attributes, including rapid evolution and adeptness at exploiting mutations. Given this parallel, we then discuss the pro- and anti-tumor roles of A3s, and suggest that lessons learned from studying A3s in the context of anti-viral immunity can be applied to tumor immunotherapy.

APOBEC3G Regulation of the Evolutionary Race Between Adaptive Immunity and Viral Immune Escape Is Deeply Imprinted in the HIV Genome

“…In addition, the analyses carried out here should be considered in the context of extensive A3 family enzyme mutations of tumor genomes, as understanding the mechanisms by which a tumor cell can escape, or boost CTL response is critical to developing vaccination and therapies based on CTL epitopes. We and others have postulated that the function of A3 family members in cancer genome mutagenesis may bear parallels to its role in viral genome mutagenesis, as tumor cells are also under pressure to avoid detection by CTL and could use A3-induced mutagenesis to this end (152–159). At present, whether and how frequently this may occur is unknown, and using similar analyses to gain insights will have important implications for the design of personalized anti-tumor CTL-based strategies.…”

RNA Editors and DNA Mutators: Cancer Heterogeneity Through Sequence Diversification

“…The APOBEC3 family was discovered soon after AID was characterized. The human genome encodes 7 APOBEC3s (3A-3D, 3F-3H), which have important roles in anti-retroviral immunity by virtue of their ability to deaminate viral DNA intermediates and hinder retroviral replication [58,59]. Specifically, upon retroviral infection and after the viral ssRNA is reverse transcribed, APOBEC3G (the founding member of the APOBEC3 family in humans) was shown to deaminate cytosines (C) to uracils (U) on the cDNA.…”

“… 7 APOBEC3s (3A-3D, 3F-3H) are encoded in the human genome [58].  Most family members have some role in anti-retroviral immunity, as they deaminate viral nucleic acid intermediates [59].…”

Evolutionary Comparative Analyses of DNA-Editing Enzymes of the Immune System: From 5-Dimensional Description of Protein Structures to Immunological Insights and Applications to Protein Engineering

“…APOBEC3s function in immune response by acting as restriction factors against viruses. They do so through mediating mutagenesis of viral genomes, or interference with the reverse transcription and integration of the viral DNA (65)(66)(67)(68). In addition the adenosine deaminases acting on double-stranded RNA (ADARs) are enzymes that mediate cellular mRNA processing through Adenosine (A) to Inosine (I) conversion; however, they have also been demonstrated to mutate viral RNA and carry out a range of cytoplasmic innate anti-viral functions (69)(70)(71)(72)(73).…”