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  • Review Article
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Retroviral restriction by APOBEC proteins

Nature Reviews Immunology volume 4, pages 868–877 (2004)Cite this article

Key Points

  • At least two human DNA-cytosine deaminases, APOBEC3F and APOBEC3G, are capable of inhibiting the infection of retroviruses such as HIV-1. This occurs by the high-frequency conversion of retroviral cDNA (minus strand) cytosines to uracils, lesions that, when replicated, result in lethal retroviral plus-strand G to A hypermutations.

  • HIV-1 and many other vertebrate lentiviruses have a counterdefence protein known as Vif (virion infectivity factor), which is able to mediate the proteasomal destruction of these APOBEC3 proteins.

  • HIV-1 Vif is not always effective, as retroviral plus-strand G to A hypermutations are commonly found in patient-derived samples.

  • These observations indicate that the in vivo balance between HIV-1 Vif and the APOBEC3 proteins might be amenable to therapeutic intervention.

  • At least nine other APOBEC3-related cytosine deaminases are encoded by the human genome, and only two of these have well-known functions. APOBEC1 edits C6666 in APOB mRNA, which results in a premature stop codon and a novel protein, whereas AID uses DNA-cytosine deamination to trigger three types of immunoglobulin-gene diversification — somatic hypermutation, gene conversion and class-switch recombination. Parallels between the innate APOBEC3-dependent restriction mechanism and the adaptive AID-dependent antibody response are striking and will probably contribute to future advances in this field.

  • Many of the other APOBEC-family cytosine deaminases probably have as-yet-unappreciated physiological roles. They might target DNA and/or RNA substrates and have important innate immune functions.

  • An examination of other vertebrate genomes shows that the APOBEC3 proteins are specific to mammals and have undergone a relatively recent evolutionary expansion (rodents have one, whereas humans and chimpanzees have eight APOBEC3 genes). We speculate that a protective role in reproduction might constitute a significant part of the selective pressure that drove this gene expansion.

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.

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Figure 1: APOBEC3G and Vif are key determinants of retroviral infectivity.
Figure 2: The human APOBECs.
Figure 3: The mechanism of Vif-dependent APOBEC3G degradation.
Figure 4: APOBECs in vertebrates.
Figure 5: Programmed immunoglobulin-gene diversification by AID.

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Acknowledgements

We are grateful to our laboratory and neighbouring colleagues for helpful comments, especially E. Hendrickson, D. Livingston, P. Magee and L. Mansky. We also thank T. Floss and the reviewers for helpful comments. R.S.H. is supported by a Burroughs–Wellcome Fund Hitchings Elion Fellowship (United States), the Searle Scholars Program (United States) and a new laboratory start-up award from the University of Minnesota (United States).

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Correspondence to Mark T. Liddament.

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DATABASES

Entrez Gene

ACF

AID

APEX

APOB

APOBEC1

APOBEC2

APOBEC3F

APOBEC3G

CCR5

CD4

CUL5

CXCR4

elongin B

elongin C

Gag

RBX1

SIV Vif

UNG2

Vif

FURTHER INFORMATION

Reuben Harris's homepage

Glossary

TARGET CELL

Any cell lacking the virus under consideration that subsequently will be infected.

APOBEC

(Apolipoprotein B (APOB) mRNA-editing, catalytic polypeptide). Although originally used to describe APOBEC1, which edits C6666 in APOB mRNA, this acronym has also become the accepted prefix for naming related vertebrate proteins that have the hallmark cytosine-deaminase motif His-X-Glu–X23–28-Pro-Cys-X2–4-Cys.

DEAMINATION

Removal of an amine group from a pyrimidine or purine nucleic-acid base. Deamination of cytosine and adenosine yields uracil and inosine, respectively.

PRODUCER CELL

Any cell used to propagate viruses.

RETROVIRUS

A class of enveloped RNA virus that is distinguished by the requirement for reverse transcription of the RNA genome by a viral reverse-transcriptase enzyme to form a DNA intermediate that is then stably integrated into host chromosomal DNA. Lentiviruses such as HIV-1 are a subset of the retrovirus family that are further distinguished by numerous accessory proteins (for example, virion infectivity factor, Vif).

MUTATIONS

Heritable changes in an organism's nucleic acid.

ACTIVATION-INDUCED DEAMINASE

(AID). A cytosine deaminase that catalyses a pivotal step in immunoglobulin gene-diversification reactions.

SOMATIC HYPERMUTATION

High-frequency base-substitution mutations found in B-cell immunoglobulin-gene variable regions.

GENE CONVERSION

A non-reciprocal recombination event between homologous or partially homologous DNA sequences, leading to the templated replacement of one sequence with the other.

CLASS-SWITCH RECOMBINATION

(Class or isotype switching). A region-specific recombination process, which occurs in antigen-activated B cells. This occurs between 'switch region' DNA sequences and results in a change from the IgM class to IgG, IgA or IgE. This imparts flexibility to the humoral immune response and allows it to exploit the different capacities of the immunoglobulins to activate the appropriate downstream effector mechanisms.

RETROVIRAL HYPERMUTATION

The high-frequency accumulation of mutations in a retroviral genome. They are distinguished from reverse-transcriptase-dependent mutations in that they are predominantly plus-strand G to A substitutions (C to T in the minus strand).

HYPERMUTATION

Levels of mutation significantly above spontaneous levels for a given system. Hypermutations are often characterized by specific local sequence preferences (biases).

MUTATOR

A protein that actively promotes mutation. This is not to be confused with DNA-repair proteins, which, with the exception of the Y-family of error-prone DNA polymerases, work to discourage mutation.

UBIQUITIN LIGASE

An enzyme (E2 or E3) that catalyses the transfer of ubiquitin — an ∼80-residue protein that is highly conserved among all living organisms — to a specific target protein, thereby modifying its function or marking it for degradation by the proteasome.

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Harris, R., Liddament, M. Retroviral restriction by APOBEC proteins. Nat Rev Immunol 4, 868–877 (2004). https://doi.org/10.1038/nri1489

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  • DOI: https://doi.org/10.1038/nri1489

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