Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Trends Biochem Sci. Author manuscript; available in PMC 2012 May 1.
Published in final edited form as:
PMCID: PMC3086942

APOBEC3G: a Double Agent in Defense


APOBEC3G (A3G) is an effective cellular host defense factor under experimental conditions in which a functional form of the HIV-encoded protein Vif cannot be expressed. Wild type Vif targets A3G for proteasomal degradation and along with it, any host defense advantage A3G might provide is severely diminished or lost. Recent evidence cast doubt on the potency of A3G in host defense and suggested that it could, under some circumstances, promote the emergence of more virulent HIV strains. In this article, I argue that it is time to recognize that A3G has the potential to act as a double agent. The path forward relies on understanding how cellular and viral regulatory mechanisms enable A3G antiviral function and on developing novel research reagents to explore these pathways.

The Multifaceted Characteristics of the Double Agent

APOBEC3G (A3G) is a member of a family of cytidine deaminases named after APOBEC11, 2, which was the first enzyme discovered with the capacity for site-specific cytidine to uridine deamination (editing) of apolipoprotein B messenger RNA. Almost nine years ago, Sheehy et al. published a paper showing that the reason why the HIV protein known as Viral infectivity factor (Vif) was required for the virus to infect nonpermissive cells was that these cells expressed A3G. Vif enabled the virus to penetrate host defenses by inducing the destruction of A3G3. At that time the story was simple and exciting: Vif induced the degradation of A3G4, 5 thus preventing A3G from being incorporated into nascent viral particles and thereby neutralizing the ability of A3G to hypermutate HIV single stranded DNA (ssDNA) post-entry during reverse transcription68 (Figure 1) (Text Box 1).

Text Box 1Deaminase-Dependent and Deaminase-Independent Antiviral Mechanisms

In the deaminase dependent mechanism, A3G catalyzes zinc-dependent hydrolytic deamination of deoxycytidine to form deoxyuridine in HIV DNA6, 7. These mutations arise primarily on the HIV minus strand due to A3G having a requirement for a ssDNA substrate8, 42. The frequency and distribution of mutations the HIV proviral DNA is determined both by the 3′ to 5′ processivity of A3G activity on ssDNA43 and limited temporally by the transient availability of ssDNA arising from RNase H-mediated removal of the RNA genome template following reverse transcription34 and prior the formation of dsDNA by second strand synthesis. A3G deaminase activity is thought to be the consequence of protein-protein and protein-ssDNA interactions that drive assembly of larger A3G-ssDNA aggregates presumed to be essential for deaminase activity8, 42, 44.

Vif is a mimic of cellular SOCS box proteins which function as receptors for protein substrates targeted for ubiquitylation through the elongin B/C–culin5–ring box protein 1(RBX2)–E3 ligase complex and degradation via the 26S proteasome45, 46. Vif–A3G binding requires residues within the N-terminus of A3G29, 4749 and residues in the N-terminus3133, 5052 and C-terminus4, 53, 54 of Vif.

In the deaminase-independent mechanism, A3G is predicted to contain an N-terminal and a C-terminal zinc-dependent deaminase or ZDD fold1. Efforts to delineate the contribution of each ZDD to antiviral activity showed that deaminase activity resided exclusively within the C-terminal ZDD15, 5557. These studies were controversial because they also suggested that deaminase activity might not be required for antiviral activity in experimental systems14, 57, 58. A3G has an intrinsic ability to nonspecifically bind RNA and ssDNA42, 56, 59, 60. This characteristic is undoubtedly essential to the deaminase-independent antiviral activities that have been described in more recent literature wherein A3G binds nucleic acids to inhibit tRNAlys3 priming of first strand synthesis61, strand transfer activity62, reverse transcript elongation63 and inhibition of double stranded proviral DNA integration64, 65.

There is agreement that protein–protein and protein–RNA interactions with the N-terminal half of A3G are required for encapsidation. However, there is disagreement over whether the interactions of A3G with Gag47, 66, 67 and/or viral RNA and/or cellular RNAs59, 60, 6871 are sufficient to place A3G, along with the viral genome, inside the virion core such that it will be ideally positioned to inhibit reverse transcription post-entry.

Figure 1
APOBEC3G During Early and Late Stages of HIV Replication

In the absence of functional Vif, A3G catalyzes dC to dU mutations primarily in the minus strand reverse transcript, and this templates dG to dA transitions in the protein coding plus strand during viral replication (Text Box 1). Some mutated virions can then integrate into the host cell chromosome, leading to the expression of viral proteins with missense substitutions or nonsense codons9, 10 (Figure 1). These findings are consistent with sequence analysis of HIV isolated from infected patients who had numerous dG to dA polymorphisms; in some instances, inactivating substitutions in the Vif sequence were identified9. The flanking nucleotide sequences of these single nucleotide polymorphisms were the same as those preferred at editing sites for A3G and its homolog A3F9. In a recent study, HIV genomes recovered from infected humanized mice expressing human A3G also contained dG to dA mutations with an A3G flanking sequence preference11. In most experimental systems, the absence of Vif enables sufficient dC to dU mutations leading to the reduction in proviral DNA due to the creation of abasic sites by uracil-DNA glycosylase which is followed by DNA degradation12, 13. In summary, A3G-mediated mutations, which occur in addition to the mutations stemming from low fidelity reverse transcription and recombination of viral genomes, were initially proposed to be solely detrimental to the virus, because of their location in the HIV genome or their abundance.

Soon after the discovery of A3G deaminase-dependent antiviral activity, experiments evaluating the functional requirement of residues in the catalytic domain of A3G through site-directed mutagenesis and deletion analyses revealed that A3G had deaminase-independent antiviral activities14, 15. A3G interactions with viral and host cell proteins and RNAs were shown to inhibit HIV reverse transcription and promote A3G assembly within viral particles (Text Box 1) (Figure 1). Proponents of the deaminase-dependent mechanism argued that deaminase-independent interactions were only apparent because of the supra physiological levels of A3G expressed in transfected cell systems1618. It is, however, inescapable that A3G subunits have an intrinsic ability to bind proteins, ssDNA and RNA, and therefore deaminase-independent interactions could occur at all levels of expression. It is also important not to overlook the fact that deaminase-independent interactions determine A3G assembly with virions: this is essential according to the deaminase-dependent hypothesis for A3G antiviral activity. What remains unclear is whether the deaminase-independent interactions of A3G that have been proposed to interfere with reverse transcription (Text Box 1) are sufficient to inhibit viral replication within the biological range of A3G expression.

Pursuing the possibility that A3G is a host defense factor, high throughput screening of chemical libraries identified small molecules with antiviral activity that were selected based on their ability to inhibit Vif-dependent A3G degradation19, 20. Similarly, a cell-transducing peptide mimic of the Vif dimerization domain was optimized21 from phage display screening of peptides that disrupted Vif multimers and thereby inhibited viral replication in nonpermissive cells. Both the small molecules and peptide had the anticipated outcome of producing virions that had a higher content of A3G and lower infectivity1921.

The opinion expressed here is that A3G has the potential of being a double agent enzyme, serving as an antiviral factor or as a facilitator of viral genome diversification which leads to the emergence of drug resistance. Sequence analysis data suggest that varying levels of A3G deaminase-dependent (and therefore deaminase-independent) activity can occur during an infection with wild type virus that expresses functional Vif. Although this theoretically could serve a host defense role, it is uncertain whether the deaminase-dependent mutagenic activity of A3G is sufficient (in activated or resting T cells for example) to exceed a mutagenic threshold for inactivating the HIV genome if the deaminase-independent activity is not sufficient to block viral replication. It should be of concern that discovery of the antiviral mechanisms has relied on overexpressing A3G or A3G mutants, or experimentally ablating A3G or Vif. Logically there is a difference between these engineered systems expressing mRNA and protein from cDNAs and a native setting in which A3G and Vif genes are both expressed and regulated during an inflammatory response. An alternative might the development of target-specific molecular probes that enable evaluating the function of A3G and Vif in native cells following infection with wild type virus. Although there are off-target and toxic artifacts possible within a drug-treatment experimental design, arguably these research reagents hold greater potential than our current approaches to reveal physiological mechanisms that are relevant to those in HIV/AIDS patients.

The Interaction of A3G with RNA Might Confound the Antiviral Mission

A3 proteins are not essential for cell survival22, but they could have important functions related to their ability to bind RNA, including the regulation of miRNA functions23 and suppression of endogenous retroviral elements2427. In fact, the ability of A3 family members to elude inactivation by viral factors such as Vif and A3G/A3F-mediated mutation of viral genomes might have contributed to the rapid evolution of primate retroviral and endogenous retroviral-like elements28. Species-specific and APOBEC3 homolog-specific29 sequence differences might help to determine the present day primate species tropism of HIV/SIV (simian immunodeficiency virus)3033.

A question that has become increasingly perplexing is why does pre-existing cellular A3G fail to deliver a preemptive antiviral strike on incoming viruses? Why is it necessary to slip a few A3G subunits into the viral particle like the proverbial Greeks in the Trojan Horse? The answer to the question might be that cellular A3G cannot gain access the nucleoprotein core of the virus where reverse transcription takes place unless it is encapsidated or the nascent ssDNA is itself shielded from cellular A3G 34. In addition, cells might regulate A3G for its interaction with cellular RNAs and this might limit the availability of A3G and/or its access to nascent single stranded proviral DNA.

At the heart of this conundrum is the seemingly contradictory concept that the intrinsic ability of A3G to bind RNA is essential for the deaminase-independent antiviral mechanism by which A3G enters the viral particle (Text Box 1) and yet binding to viral RNA in the capsid or binding to cellular RNAs inhibits A3G deaminase-dependent mutagenesis of ssDNA during reverse transcription (Text Box 2). Different cells can regulate the interaction of A3G with cellular RNAs in contrasting ways to generate low molecular mass (LMM) forms of A3G (relatively free of RNA) and high molecular mass (HMM) aggregates of A3G bound to RNA in ribonucleoprotein (RNP) complexes (Text Box 2) (Figure 1). The larger aggregates colocalize with cytoplasmic P-Bodies and Stress Granules that function in RNA and RNP protein degradation and/or serve as temporary storage depots. In HMM aggregates, A3G is believed to have little or no antiviral activity yet Vif mediates A3G degradation in both the LMM and HMM forms 18.

Text Box 2Ribonucleoprotein Complexes Containing A3G

Purified A3G forms homomultimers in a concentration-dependent manner through protein–protein interactions72, 73. Binding of either RNA or ssDNA to A3G will promote higher order oligomerization of A3G subunits as evidenced under defined in vitro conditions by native gel shift analyses42 and atomic force microscopy44. RNP complexes containing A3G referred to as high molecular mass (HMM) complexes colocalize with P-bodies and Stress Granules43, 44, 7479 where cells degrade or recycle RNAs and RNP proteins. Glycerol gradient sedimentation or size exclusion chromatography of cell extracts have demonstrated that A3G associates with these megaDaltonsized RNPs within minutes of its translation17, 18.

Whereas HMM A3G predominates in cells that are permissive to HIV infection, cell types considered to be refractory to HIV infection (e.g., resting CD4+ T cells, monocytes and mature dendritic cells74, 76, 79) maintain A3G as a component of low molecular mass (LMM) complexes. Through mechanisms that are not understood, cytokines, double stranded RNAs and other growth factors regulate the expression of A3G and the inter-conversion of LMM and HMM complexes. The significance of the inter-conversion of A3G aggregation states to its antiviral activity is currently an underdeveloped issue that needs further investigation36, 37.

All or most of the conversion of LMM to HMM complexes is attributable to RNA-bridged A3G oligomerization and to date no protein components of P-bodies or Stress Granules have been shown to bind directly to A3G. As part of HMM complexes, A3G has low or no deaminase activity, but RNase digestion of isolated HMM complexes restores deaminase activity73, 74.

The higher level of deaminase activity in LMM A3G and its prevalence in nonpermissive cells led to the hypothesis that LMM A3G was necessary and sufficient for cells to be refractory to HIV infection. However, this has been retracted35. Recent experiments testing the hypothesis showed that an aggressive knockdown of LMM A3G in resting CD4+ T cells by RNAi or Vif-mediated degradation of A3G did not render these cells permissive to HIV infection36, 37. The implication of the new data is that LMM A3G pre-existing in cells is not sufficiently available or active enough to inhibit HIV replication.

The new data raise an important question: if A3G in nonpermissive cells is not sufficient to inhibit viral replication, does it have no activity at all, or does it have a low level of mutagenic activity? This is an important question because earlier studies (reviewed in38) warned that rather than providing antiviral host defense, A3G/A3F activities might diversify the viral genome, a tenet predicted by evolutionary biologists studying retroviruses and retroviral elements28. Recent papers have confirmed this possibility under experimental conditions where A3G/A3F promoted mutations that benefited HIV39, 40 and induced a drug-resistant phenotype41. The available data support the possibility that the activity of LMM A3G in infected nonpermissive cells is sufficient to promote mutations in the HIV genome. Moreover, the new data suggest that the mutational activity might not be sufficient to inhibit viral replication either during early or late stages of the viral life cycle (Figure 1).

Embracing the Uncertainty with a View Toward Proactive Intervention

The important question before us is what level of A3G mutagenic activity might benefit the virus compared to what is necessary to inhibit viral replication? The simplest answer might be that a little DNA deaminase activity benefits the virus and a high level of activity destroys the virus. Unfortunately, we do not know what these levels are, and the location of mutations within the viral genome can be more important than how many mutations there are. To explore this possibility, future research should determine the naturally occurring mechanisms regulating the interconversion of HMM and LMM and how this might determine A3G mutagenic activity. Based on the results, we should gain an understanding of the paradoxical situation wherein A3G host defense mechanisms are sequestered in RNPs and inactivated in permissive cells during an HIV infection. The results will have a significant impact on translational research and therapeutic development using A3G/Vif as a target.

From one point of view, the available data suggest that if naturally expressed A3G activity is too low to provide host defense, inhibiting Vif alone might have limited immediate therapeutic value and could have the unintended long-term consequence of aiding the virus. Conceptually one therapeutic strategy might be to inhibit A3G deaminase activity and allow Vif to destroy A3G. This might hold the potential of reducing the emergence of viral resistance in patients who are also receiving other modalities of antiretroviral therapy. The significant challenge here is that deaminase inhibitors would have to be developed that are selective for A3G/A3F so that they will not be cytotoxic to intermediary metabolism. Skeptics will argue that inhibiting a host defense factor because it might induce beneficial mutations in the virus ignores the greater possibility that A3G mutations might, overall, be deleterious to the virus.

An alternative approach is to activate A3G HMM mutagenic efficiency and enhance its access to viral replication complexes. Could such activators enable cells to ‘fight back’ even though Vif is destroying A3G? In this case, combining A3G activators with Vif inhibitors might address both the need to reduce viral infection and lessen the frequency with which drug resistant strains emerge. Similar to deaminase inhibitors, deaminase activators will need to be A3G/A3F specific.

It is vital that efforts continue to be made to explore cellular and viral factors that regulate the double agent A3G. Undoubtedly, the development of novel probes and research reagents will be crucial to our understanding of mechanisms that determine what role A3G plays in infected cells. Despite progress in these areas, the therapeutic value of A3G inhibitors or activators, with or without Vif antagonists, will not be fully appreciated until such compounds are tested in clinical trials.


The author thanks Jenny M.L. Smith for the illustrations. The author is grateful to Steve Dewhurst, Jason Salter, Jenny Smith and members of the Smith and Wedekind laboratories and OyaGen, Inc for critical reading of the manuscript. This work was supported by Public Health Service grants (NIAID R21 058789, NINDS R21 067671) and the Bill and Melinda Gates foundation grant awarded to HCS, a Public Health Services grant (NIAID R21/R33 076085) awarded to Joseph E. Wedekind and a Public Health Services T32 training grant (NIAID 049815) and Developmental Center for AIDS Research grant (NIAID P30 078498) awarded to Steve Dewhurst.


A family of proteins containing a zinc-dependent deaminase motif, named after the first enzyme in the family discovered, apolipoprotein B editing catalytic subunit 1. The family consists of activation induced deaminase (AID), A1, A2, A3A–A3H and A4. Although A3G and A3F have a high level of identity and similar structural organization, they have different nearest neighbor preferences in ssDNA for deamination and are different in their interaction with Vif: A3G is more susceptible to Vif-dependent degradation. A3G protein is natively expressed at higher levels than A3F
High Molecular Mass and Low Molecular Mass complexes (respectively) are operationally defined by biochemical sizing methods of A3G in cell extracts. They range in size from megaDaltons to several hundred kiloDaltons for HMM and a few hundred kiloDaltons to single subunits of A3G (46 kDa) for LMM. A3G HMM is heterogeneous in protein composition because A3G binds nonselectively to cellular RNAs which in turn are associated with variety of cellular proteins. A3G LMM is considered to have few or no RNAs associated with A3G subunits
Permissive and Nonpermissive Cells
An operational term used to describe the ability of a cell to undergo a productive infection by a particular retrovirus (permissive) or not (nonpermissive)
Proviral DNA
The double stranded DNA copy of the retroviral RNA genome
SOCS Box protein
A member of a family of proteins containing the Suppressor of Cytokine Signaling amino acid motif. SOCS box-containing proteins are known to mediate an interaction between protein substrates targeted for degradation and the respective components of the ubiquitylation machinery. They do so by binding to protein substrates as well as elongin B/C proteins, cullin 5, and RBX2, which together interact with an E3 ubiquitin-protein ligase complex. There is a large diversity of SOCS box-containing proteins that serve as receptors for docking different substrates into the ubiquitylation machinery. Vif mimics these receptors when it binds A3G, thereby inducing its destruction
Vif (Viral infectivity factor)
a 21 kDa HIV-encoded protein containing multiple domains for diverse protein–protein and protein–RNA interactions
Viral Capsid
The retroviral RNA genome encased in an oligomeric viral protein shell minus the components that make up the viral envelope of the mature viral particle or virion
Viral Replication
An inclusive term referring to the entire viral life cycle and not limited to reverse transcription
ZDD (Zinc dependent-deaminase)
A sequence that is part of the cytidine deaminase protein fold consisting of five anti-parallel beta sheets supported by two alpha helices that position three cysteine/histidine residues for the coordination of a zinc atom, a water molecule and a glutamic acid residue for proton shuttling in a hydrolytic deamination reaction leading to the conversion of cytidine/deoxycytidine to uridine/deoxyuridine with NH3 as the leaving group


Conflict of Interest Statement

H.C. Smith is a full time faculty member in the Department of Biochemistry and Biophysics and the Center for RNA Biology at the University of Rochester, School of Medicine and Dentistry, Rochester, NY. He is also founder of OyaGen, Inc and a consultant for the company as its chief scientific officer. OyaGen, Inc, is a therapeutic development company seeking novel therapeutics using APOBEC editing mechanisms as targets (

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


1. Wedekind JE, et al. Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business. Trends Genet. 2003;19:207–216. [PubMed]
2. Smith HC. The APOBEC1 Paradigm for Mammalian Cytidine Deaminases that Edit DNA and RNA. Landes bioScience 2009
3. Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002;418:646–650. [PubMed]
4. Yu Y, et al. Selective assembly of HIV-1 Vif-Cul5-ElonginB-ElonginC E3 ubiquitin ligase complex through a novel SOCS box and upstream cysteines. Genes Dev. 2004;18:2867–2872. [PubMed]
5. Stopak K, De Noronha C, Yonemoto W, Greene WC. HIV-1 Vif Blocks the Antiviral Activity of APOBEC3G by Impairing both Its Translation and Intracellular Stability. Mol Cell. 2003;12:591–601. [PubMed]
6. Zhang H, et al. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature. 2003;424:94–98. [PMC free article] [PubMed]
7. Mangeat B, et al. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature. 2003;424:99–103. [PubMed]
8. Yu Q, et al. Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome. Nat Struct Mol Biol. 2004;11:435–442. [PubMed]
9. Simon V, et al. Natural variation in Vif: differential impact on APOBEC3G/3F and a potential role in HIV-1 diversification. PLoS Pathog. 2005;1:e6. [PMC free article] [PubMed]
10. Pace C, et al. Population level analysis of human immunodeficiency virus type 1 hypermutation and its relationship with APOBEC3G and vif genetic variation. J Virol. 2006;80:9259–9269. [PMC free article] [PubMed]
11. Sato KIT, Misawa N, Kobayashi T, Yamashita Y, Ohmichi M, Ito M, Takaori-Kondo A, Koyanagi Y. Remarkable letha G-to-A mutations in vif-proficient HIV-1 provirus by individual APOBEC3 proteins in humanized mice. J Virol. 2010 Epub ahead of print. [PMC free article] [PubMed]
12. Simon JH, Malim MH. The human immunodeficiency virus type 1 Vif protein modulates the postpenetration stability of viral nucleoprotein complexes. J Virol. 1996;70:5297–5305. [PMC free article] [PubMed]
13. Gaddis NC, et al. Comprehensive Investigation of the Molecular Defect in vif-Deficient Human Immunodeficiency Virus Type 1 Virions. J Virol. 2003;77:5810–5820. [PMC free article] [PubMed]
14. Shindo K, et al. The enzymatic activity of CEM15/Apobec-3G is essential for the regulation of the infectivity of HIV-1 virion but not a sole determinant of its antiviral activity. J Biol Chem. 2003;278:44412–44416. [PubMed]
15. Li J, et al. Functional domains of APOBEC3G required for antiviral activity. J Cell Biochem. 2004;92:560–572. [PubMed]
16. Browne EP, et al. Restriction of HIV-1 by APOBEC3G is cytidine deaminase-dependent. Virology. 2009;387:313–321. [PMC free article] [PubMed]
17. Soros VB, et al. Newly synthesized APOBEC3G is incorporated into HIV virions, inhibited by HIV RNA, and subsequently activated by RNase H. PLoS Pathog. 2007;3:e15. [PubMed]
18. Goila-Gaur R, et al. Differential sensitivity of “old” versus “new” APOBEC3G to human immunodeficiency virus type 1 vif. J Virol. 2009;83:1156–1160. [PMC free article] [PubMed]
19. Cen S, et al. Small molecular inhibitors for HIV-1 replication through specifically stabilizing APOBEC3G. J Biol Chem. 2010;285:16546–16552. [PMC free article] [PubMed]
20. Nathans R, et al. Small-molecule inhibition of HIV-1 Vif. Nat Biotechnol. 2008;26:1187–1192. [PMC free article] [PubMed]
21. Miller JH, et al. The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G. Retrovirology. 2007;4:81. [PMC free article] [PubMed]
22. Mikl MC, et al. Mice deficient in APOBEC2 and APOBEC3. Mol Cell Biol. 2005;25:7270–7277. [PMC free article] [PubMed]
23. Huang J, et al. Derepression of microRNA-mediated protein translation inhibition by apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) and its family members. J Biol Chem. 2007;282:33632–33640. [PubMed]
24. Muckenfuss H, et al. APOBEC3 proteins inhibit human LINE-1 retrotransposition. Journal of Biological Chemistry. 2006;281:22161–22172. [PubMed]
25. Chiu YL, et al. High-molecular-mass APOBEC3G complexes restrict Alu retrotransposition. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:15588–15593. [PubMed]
26. Esnault C, et al. APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses. Nature. 2005;433:430–433. [PubMed]
27. Niewiadomska AM, et al. Differential inhibition of long interspersed element 1 by APOBEC3 does not correlate with high-molecular-mass-complex formation or P-body association. J Virol. 2007;81:9577–9583. [PMC free article] [PubMed]
28. Sawyer SL, et al. Ancient adaptive evolution of the primate antiviral DNA-editing enzyme APOBEC3G. PLoS Biol. 2004;2:E275. [PMC free article] [PubMed]
29. Russell RA, Pathak VK. Identification of two distinct human immunodeficiency virus type 1 Vif determinants critical for interactions with human APOBEC3G and APOBEC3F. J Virol. 2007;81:8201–8210. [PMC free article] [PubMed]
30. Mariani R, et al. Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell. 2003;114:21–31. [PubMed]
31. Xu H, et al. A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion. Proc Natl Acad Sci U S A. 2004;101:5652–5657. [PubMed]
32. Mangeat B, et al. A single amino acid determinant governs the species-specific sensitivity of APOBEC3G to Vif action. J Biol Chem. 2004;279:14481–14483. [PubMed]
33. Bogerd HP, et al. A single amino acid difference in the host APOBEC3G protein controls the primate species specificity of HIV type 1 virion infectivity factor. Proc Natl Acad Sci U S A. 2004;101:3770–3774. [PubMed]
34. Hu C, et al. The HIV-1 central polypurine tract functions as a second line of defense against APOBEC3G/F. J Virol. 2010;84:11981–11993. [PMC free article] [PubMed]
35. Chiu YL, Soros VB, Kreisberg JF, Stopak K, Yonemoto W, Greene WC. Retraction of Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells. Nature. 2010;435(7038):108–14. [PubMed]Nature. 466:276. [PubMed]
36. Kamata M, et al. Reassessing the role of APOBEC3G in human immunodeficiency virus type 1 infection of quiescent CD4+ T-cells. PLoS Pathog. 2009;5:e1000342. [PMC free article] [PubMed]
37. Santoni de Sio FR, Trono D. APOBEC3G-depleted resting CD4+ T cells remain refractory to HIV1 infection. PLoS One. 2009;4:e6571. [PMC free article] [PubMed]
38. Pillai SK, et al. Turning up the volume on mutational pressure: is more of a good thing always better? (A case study of HIV-1 Vif and APOBEC3) Retrovirology. 2008;5:26. [PMC free article] [PubMed]
39. Albin JHG, Hultquist J, Brown W, Harris R. Long-term restriction by APOBEC3F selects human immunodeficiency virus type 1 variants with restored Vif function. J Virol. 2010;84:10209–10219. [PMC free article] [PubMed]
40. Kim E-YBT, Kunstman K, Swantek P, Koning F, Malim M, Wolinsky S. Human APOBEC3G-mediated editing can promote HIV-1 sequence diversification and accelerate adaptation to selective pressure. J Virol. 2010;84:10402–10405. [PMC free article] [PubMed]
41. Sadler HSM, Harris R, Mansky L. APOBEC3G contributes to HIV-1 variation through sublethal mutagenesis. J Virol. 2010;84:7396–7404. [PMC free article] [PubMed]
42. Iwatani Y, et al. Biochemical activities of highly purified, catalytically active human APOBEC3G: correlation with antiviral effect. J Virol. 2006;80:5992–6002. [PMC free article] [PubMed]
43. Chelico L, et al. APOBEC3G DNA deaminase acts processively 3′ --> 5′ on single-stranded DNA. Nat Struct Mol Biol. 2006;13:392–399. [PubMed]
44. Chelico L, et al. A structural model for deoxycytidine deamination mechanisms of the HIV-1 inactivation enzyme APOBEC3G. J Biol Chem. 2010;285:16195–16205. [PMC free article] [PubMed]
45. Yu X, et al. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science. 2003;302:1056–1060. [PubMed]
46. Mehle A, et al. Vif overcomes the innate antiviral activity of APOBEC3G by promoting its degradation in the ubiquitin-proteasome pathway. J Biol Chem. 2004;279:7792–7798. [PubMed]
47. Huthoff H, Malim MH. Identification of amino acid residues in APOBEC3G required for regulation by human immunodeficiency virus type 1 Vif and Virion encapsidation. J Virol. 2007;81:3807–3815. [PMC free article] [PubMed]
48. Zhang L, et al. Function analysis of sequences in human APOBEC3G involved in Vif-mediated degradation. Virology. 2008;370:113–121. [PubMed]
49. Santa-Marta M, et al. HIV-1 Vif can directly inhibit apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G-mediated cytidine deamination by using a single amino acid interaction and without protein degradation. J Biol Chem. 2005;280:8765–8775. [PubMed]
50. Schrofelbauer B, et al. Mutational alteration of human immunodeficiency virus type 1 Vif allows for functional interaction with nonhuman primate APOBEC3G. J Virol. 2006;80:5984–5991. [PMC free article] [PubMed]
51. Chen G, et al. A patch of positively charged amino acids surrounding the human immunodeficiency virus type 1 Vif SLVx4Yx9Y motif influences its interaction with APOBEC3G. J Virol. 2009;83:8674–8682. [PMC free article] [PubMed]
52. Tian C, et al. Differential requirement for conserved tryptophans in human immunodeficiency virus type 1 Vif for the selective suppression of APOBEC3G and APOBEC3F. J Virol. 2006;80:3112–3115. [PMC free article] [PubMed]
53. Mehle A, et al. Phosphorylation of a novel SOCS-box regulates assembly of the HIV-1 Vif-Cul5 complex that promotes APOBEC3G degradation. Genes Dev. 2004;18:2861–2866. [PubMed]
54. Wolfe LS, et al. Dissection of the HIV Vif interaction with human E3 ubiquitin ligase. J Virol. 2010;84:7135–7139. [PMC free article] [PubMed]
55. Hache G, et al. The retroviral hypermutation specificity of APOBEC3F and APOBEC3G is governed by the C-terminal DNA cytosine deaminase domain. Journal of Biological Chemistry. 2005;280:10920–10924. [PubMed]
56. Navarro F, et al. Complementary function of the two catalytic domains of APOBEC3G. Virology. 2005;333:374–386. [PubMed]
57. Newman EN, et al. Antiviral function of APOBEC3G can be dissociated from cytidine deaminase activity. Curr Biol. 2005;15:166–170. [PubMed]
58. Bishop KN, et al. Antiviral potency of APOBEC proteins does not correlate with cytidine deamination. J Virol. 2006;80:8450–8458. [PMC free article] [PubMed]
59. Khan MA, et al. Analysis of the contribution of cellular and viral RNA to the packaging of APOBEC3G into HIV-1 virions. Retrovirology. 2007;4:48. [PMC free article] [PubMed]
60. Svarovskaia ES, et al. Human apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is incorporated into HIV-1 virions through interactions with viral and nonviral RNAs. J Biol Chem. 2004;279:35822–35828. [PubMed]
61. Guo F, et al. The interaction of APOBEC3G with human immunodeficiency virus type 1 nucleocapsid inhibits tRNA3Lys annealing to viral RNA. J Virol. 2007;81:11322–11331. [PMC free article] [PubMed]
62. Li XY, et al. APOBEC3G inhibits DNA strand transfer during HIV-1 reverse transcription. J Biol Chem. 2007;282:32065–32074. [PubMed]
63. Bishop KN, et al. APOBEC3G inhibits elongation of HIV-1 reverse transcripts. PLoS Pathog. 2008;4:e1000231. [PMC free article] [PubMed]
64. Mbisa JBR, Thomas J, Vandergraaff N, Dorweiler I, Svarovskaia E, Brown W, Mansky L, Gorelick R, Harris R, Engelman R, Pathak V. HIV-1 cDNAs produced in the presence of APOBEC3G exhibit defects in plus-strand DNA transfer and integration. J Virol. 2007;81:7099–7110. [PMC free article] [PubMed]
65. Luo K, et al. Cytidine deaminases APOBEC3G and APOBEC3F interact with human immunodeficiency virus type 1 integrase and inhibit proviral DNA formation. J Virol. 2007;81:7238–7248. [PMC free article] [PubMed]
66. Alce TM, Popik W. APOBEC3G is incorporated into virus-like particles by a direct interaction with HIV-1 Gag nucleocapsid protein. J Biol Chem. 2004;279:34083–34086. [PubMed]
67. Cen S, et al. The interaction between HIV-1 Gag and APOBEC3G. J Biol Chem. 2004;279:33177–33184. [PubMed]
68. Bogerd HP, Cullen BR. Single-stranded RNA facilitates nucleocapsid: APOBEC3G complex formation. RNA. 2008;14:1228–1236. [PubMed]
69. Huthoff H, et al. RNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1. PLoS Pathog. 2009;5:e1000330. [PMC free article] [PubMed]
70. Wang T, et al. 7SL RNA mediates virion packaging of the antiviral cytidine deaminase APOBEC3G. J Virol. 2007;81:13112–13124. [PMC free article] [PubMed]
71. Bach D, et al. Characterization of APOBEC3G binding to 7SL RNA. Retrovirology. 2008;5:54. [PMC free article] [PubMed]
72. Salter JD, et al. A hydrodynamic analysis of APOBEC3G reveals a monomer-dimer-tetramer self-association that has implications for anti-HIV function. Biochemistry. 2009;48:10685–10687. [PMC free article] [PubMed]
73. Wedekind JE, et al. Nanostructures of APOBEC3G support a hierarchical assembly model of high molecular mass ribonucleoprotein particles from dimeric subunits. Journal of Biological Chemistry. 2006;281:38122–38126. [PMC free article] [PubMed]
74. Kreisberg JF, et al. Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high molecular mass APOBEC3G complex formation. J Exp Med. 2006;203:865–870. [PMC free article] [PubMed]
75. Wichroski MJ, et al. Human retroviral host restriction factors APOBEC3G and APOBEC3F localize to mRNA processing bodies. PLoS Pathog. 2006;2:e41. [PubMed]
76. Stopak KS, et al. Distinct patterns of cytokine regulation of APOBEC3G expression and activity in primary lymphocytes, macrophages, and dendritic cells. J Biol Chem. 2007;282:3539–3546. [PubMed]
77. Kozak SL, et al. The anti-HIV-1 editing enzyme APOBEC3G binds HIV-1 RNA and messenger RNAs that shuttle between polysomes and stress granules. J Biol Chem. 2006;281:29105–29119. [PubMed]
78. Gallois-Montbrun S, et al. Antiviral protein APOBEC3G localizes to ribonucleoprotein complexes found in P bodies and stress granules. J Virol. 2007;81:2165–2178. [PMC free article] [PubMed]
79. Vetter ML, D'Aquila RT. Cytoplasmic APOBEC3G restricts incoming Vif-positive human immunodeficiency virus type 1 and increases two-long terminal repeat circle formation in activated T-helper-subtype cells. J Virol. 2009;83:8646–8654. [PMC free article] [PubMed]