View source for APOBEC3G

{{Short description|Protein and coding gene in humans}}
{{Infobox_gene}}

'''APOBEC3G''' (apolipoprotein B mRNA editing enzyme, catalytic subunit 3G) is a human [[enzyme]] encoded by the '''''APOBEC3G''''' [[gene]] that belongs to the [[APOBEC]] superfamily of [[protein]]s.<ref name="pmid12167863">{{cite journal | vauthors = Sheehy AM, Gaddis NC, Choi JD, Malim MH | title = Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein | journal = Nature | volume = 418 | issue = 6898 | pages = 646–50 | date = August 2002 | pmid = 12167863 | doi = 10.1038/nature00939 | bibcode = 2002Natur.418..646S | s2cid = 4403228 }}</ref> This family of proteins has been suggested to play an important role in innate anti-viral [[immunity (medical)|immunity]].<ref name="pmid16557012">{{cite journal | vauthors = Takaori A | title = [Antiviral defense by APOBEC3 family proteins] | language = ja | journal = Uirusu | volume = 55 | issue = 2 | pages = 267–72 | date = December 2005 | pmid = 16557012 | doi = 10.2222/jsv.55.267 | doi-access = free }}</ref> APOBEC3G belongs to the family of cytidine deaminases that catalyze the deamination of cytidine to uridine in the single stranded DNA substrate.<ref name="pmid12167863"/> The C-terminal domain of A3G renders catalytic activity, several NMR and crystal structures explain the substrate specificity and catalytic activity.<ref name="pmid23787464">{{cite journal | vauthors = Vasudevan AA, Smits SH, Höppner A, Häussinger D, Koenig BW, Münk C | title = Structural features of antiviral DNA cytidine deaminases | journal = Biological Chemistry | volume = 394 | issue = 11 | pages = 1357–70 | date = November 2013 | pmid = 23787464 | doi = 10.1515/hsz-2013-0165 | s2cid = 4151961 | url = http://juser.fz-juelich.de/record/139785/files/FZJ-2013-05757.pdf }}</ref><ref name="pmid18288108">{{cite journal | vauthors = Chen KM, Harjes E, Gross PJ, Fahmy A, Lu Y, Shindo K, Harris RS, Matsuo H | display-authors = 6 | title = Structure of the DNA deaminase domain of the HIV-1 restriction factor APOBEC3G | journal = Nature | volume = 452 | issue = 7183 | pages = 116–9 | date = March 2008 | pmid = 18288108 | doi = 10.1038/nature06638 | bibcode = 2008Natur.452..116C | s2cid = 4345410 }}</ref><ref name="pmid20152150">{{cite journal | vauthors = Shandilya SM, Nalam MN, Nalivaika EA, Gross PJ, Valesano JC, Shindo K, Li M, Munson M, Royer WE, Harjes E, Kono T, Matsuo H, Harris RS, Somasundaran M, Schiffer CA | display-authors = 6 | title = Crystal structure of the APOBEC3G catalytic domain reveals potential oligomerization interfaces | journal = Structure | volume = 18 | issue = 1 | pages = 28–38 | date = January 2010 | pmid = 20152150 | pmc = 2913127 | doi = 10.1016/j.str.2009.10.016 }}</ref><ref name="pmid18849968">{{cite journal | vauthors = Holden LG, Prochnow C, Chang YP, Bransteitter R, Chelico L, Sen U, Stevens RC, Goodman MF, Chen XS | display-authors = 6 | title = Crystal structure of the anti-viral APOBEC3G catalytic domain and functional implications | journal = Nature | volume = 456 | issue = 7218 | pages = 121–4 | date = November 2008 | pmid = 18849968 | pmc = 2714533 | doi = 10.1038/nature07357 | bibcode = 2008Natur.456..121H }}</ref><ref name="pmid19153609">{{cite journal | vauthors = Furukawa A, Nagata T, Matsugami A, Habu Y, Sugiyama R, Hayashi F, Kobayashi N, Yokoyama S, Takaku H, Katahira M | display-authors = 6 | title = Structure, interaction and real-time monitoring of the enzymatic reaction of wild-type APOBEC3G | journal = The EMBO Journal | volume = 28 | issue = 4 | pages = 440–51 | date = February 2009 | pmid = 19153609 | pmc = 2646150 | doi = 10.1038/emboj.2008.290 }}</ref><ref name="pmid19389408">{{cite journal | vauthors = Harjes E, Gross PJ, Chen KM, Lu Y, Shindo K, Nowarski R, Gross JD, Kotler M, Harris RS, Matsuo H | display-authors = 6 | title = An extended structure of the APOBEC3G catalytic domain suggests a unique holoenzyme model | journal = Journal of Molecular Biology | volume = 389 | issue = 5 | pages = 819–32 | date = June 2009 | pmid = 19389408 | pmc = 2700007 | doi = 10.1016/j.jmb.2009.04.031 }}</ref><ref name="pmid22181350">{{cite journal | vauthors = Li M, Shandilya SM, Carpenter MA, Rathore A, Brown WL, Perkins AL, Harki DA, Solberg J, Hook DJ, Pandey KK, Parniak MA, Johnson JR, Krogan NJ, Somasundaran M, Ali A, Schiffer CA, Harris RS | display-authors = 6 | title = First-in-class small molecule inhibitors of the single-strand DNA cytosine deaminase APOBEC3G | journal = ACS Chemical Biology | volume = 7 | issue = 3 | pages = 506–17 | date = March 2012 | pmid = 22181350 | pmc = 3306499 | doi = 10.1021/cb200440y }}</ref><ref name="Retroviral restriction by APOBEC pr">{{cite journal | vauthors = Harris RS, Liddament MT | title = Retroviral restriction by APOBEC proteins | journal = Nature Reviews. Immunology | volume = 4 | issue = 11 | pages = 868–77 | date = November 2004 | pmid = 15516966 | doi = 10.1038/nri1489 | s2cid = 10789405 }}</ref>

APOBEC3G exerts innate [[antiretroviral]] immune activity against [[retrovirus]]es, most notably [[HIV]], by interfering with proper replication. However, [[lentiviruses]] such as HIV have evolved the [[Viral infectivity factor]] (Vif) protein in order to counteract this effect. Vif interacts with APOBEC3G and triggers the [[ubiquitination]] and degradation of APOBEC3G via the proteasomal pathway.<ref name="pmid18499212">{{cite journal | vauthors = Donahue JP, Vetter ML, Mukhtar NA, D'Aquila RT | title = The HIV-1 Vif PPLP motif is necessary for human APOBEC3G binding and degradation | journal = Virology | volume = 377 | issue = 1 | pages = 49–53 | date = July 2008 | pmid = 18499212 | pmc = 2474554 | doi = 10.1016/j.virol.2008.04.017 }}</ref> On the other hand, [[Human foamy virus|foamy virus]]es produce an [[accessory protein Bet]] ({{UniProt|P89873}}) that impairs the cytoplasmic solubility of APOBEC3G.<ref name="pmid23760237">{{cite journal | vauthors = Jaguva Vasudevan AA, Perkovic M, Bulliard Y, Cichutek K, Trono D, Häussinger D, Münk C | title = Prototype foamy virus Bet impairs the dimerization and cytosolic solubility of human APOBEC3G | journal = Journal of Virology | volume = 87 | issue = 16 | pages = 9030–40 | date = August 2013 | pmid = 23760237 | pmc = 3754047 | doi = 10.1128/JVI.03385-12 }}</ref> The two ways of inhibition are distinct from each other, but they can replace each other ''in vivo''.<ref>{{cite journal | vauthors = Ledesma-Feliciano C, Hagen S, Troyer R, Zheng X, Musselman E, Slavkovic Lukic D, Franke AM, Maeda D, Zielonka J, Münk C, Wei G, VandeWoude S, Löchelt M | display-authors = 6 | title = Replacement of feline foamy virus bet by feline immunodeficiency virus vif yields replicative virus with novel vaccine candidate potential | journal = Retrovirology | volume = 15 | issue = 1 | pages = 38 | date = May 2018 | pmid = 29769087 | doi = 10.1186/s12977-018-0419-0 | pmc = 5956581 | doi-access = free }}</ref>

== Discovery ==

It was first identified by Jarmuz ''et al.''<ref name="pmid11863358">{{cite journal | vauthors = Jarmuz A, Chester A, Bayliss J, Gisbourne J, Dunham I, Scott J, Navaratnam N | title = An anthropoid-specific locus of orphan C to U RNA-editing enzymes on chromosome 22 | journal = Genomics | volume = 79 | issue = 3 | pages = 285–96 | date = March 2002 | pmid = 11863358 | doi = 10.1006/geno.2002.6718 }}</ref> as a member of  family of proteins APOBEC3A to 3G  on chromosome 22 in 2002 and later also as a cellular factor able to restrict replication of HIV-1 lacking the viral accessory protein [[Viral infectivity factor|Vif]].  Soon after, it was shown that APOBEC3G belonged to a family of proteins grouped together due to their homology with the [[cytidine deaminase]] [[APOBEC1]].

== Structure ==

<!-- Deleted image removed: [[File:N-terminal catalytic domain.jpg|thumb|left|upright=1|alt=APOBEC3G CD1| Figure 1: "Structure model of the N-terminal [catalytic deaminase domain]  of [APOBEC3G]. Zinc-coordinating residues are indicated by circles, α-helices are in yellow, and  β-strands are in pink. The position of residue D128 is indicated in the predicted loop between β4 and α3."<ref name="pmid17267497"/>]] -->

APOBEC3G has a symmetric structure, resulting in 2 homologous [[catalytic]] domains, the N-terminal (CD1) and C-terminal (CD2) domains, each of which contains a [[Zinc|{{chem|Zn|2+}}]] coordination site.<ref name="pmid18789977">{{cite journal | vauthors = Greene WC, Debyser Z, Ikeda Y, Freed EO, Stephens E, Yonemoto W, Buckheit RW, Esté JA, Cihlar T | display-authors = 6 | title = Novel targets for HIV therapy | journal = Antiviral Research | volume = 80 | issue = 3 | pages = 251–65 | date = December 2008 | pmid = 18789977 | doi = 10.1016/j.antiviral.2008.08.003 | url = https://zenodo.org/record/3414333 }}</ref> Each domain also has the typical His/Cys-X-Glu-X23–28-Pro-Cys-X2-Cys motif for cytidine deaminases. However, unlike the typical cytidine deaminases, APOBEC3G contains a unique [[alpha helix]] between two [[beta sheet]]s in the catalytic domain that could be a [[cofactor (biochemistry)|cofactor]] binding site.<ref name="pmid15780864">{{cite journal | vauthors = Huthoff H, Malim MH | title = Cytidine deamination and resistance to retroviral infection: towards a structural understanding of the APOBEC proteins | journal = Virology | volume = 334 | issue = 2 | pages = 147–53 | date = April 2005 | pmid = 15780864 | doi = 10.1016/j.virol.2005.01.038 | doi-access = free }}</ref> (Figure 1)

CD2 is catalytically active and vital for deamination and motif specificity. CD1 is catalytically inactive, but very important for binding to [[DNA]] and [[RNA]] and is key to defining the 5'->3' processivity of APOBEC3G deamination.<ref name="pmid20212048">{{cite journal | vauthors = Chelico L, Prochnow C, Erie DA, Chen XS, Goodman MF | title = Structural model for deoxycytidine deamination mechanisms of the HIV-1 inactivation enzyme APOBEC3G | journal = The Journal of Biological Chemistry | volume = 285 | issue = 21 | pages = 16195–205 | date = May 2010 | pmid = 20212048 | pmc = 2871487 | doi = 10.1074/jbc.M110.107987 | doi-access = free }}</ref> CD2 has no deaminase activity without the presence of CD1.<ref name="pmid21489586">{{cite journal | vauthors = Li X, Ma J, Zhang Q, Zhou J, Yin X, Zhai C, You X, Yu L, Guo F, Zhao L, Li Z, Zeng Y, Cen S | display-authors = 6 | title = Functional analysis of the two cytidine deaminase domains in APOBEC3G | journal = Virology | volume = 414 | issue = 2 | pages = 130–6 | date = June 2011 | pmid = 21489586 | doi = 10.1016/j.virol.2011.03.014 | doi-access = free }}</ref>

Native APOBEC3G is composed of [[monomer]]s, [[Protein dimer|dimer]]s, [[Protein trimer|trimer]]s, [[Protein tetramer|tetramer]]s, and higher order [[oligomer]]s. While it is thought that APOBEC3G functions as a dimer, it is possible that it actually functions as a mix of monomers and oligomers.<ref name="pmid20212048"/>

The D128 [[amino acid]] residue, which lies within CD1 (Figure 1), appears to be particularly important for APOBEC3G interactions with Vif because a D128K point mutation prevents Vif-dependent depletion of APOBEC3G.<ref>{{cite journal | vauthors = Mariani R, Chen D, Schröfelbauer B, Navarro F, König R, Bollman B, Münk C, Nymark-McMahon H, Landau NR | display-authors = 6 | title = Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif | journal = Cell | volume = 114 | issue = 1 | pages = 21–31 | date = July 2003 | pmid = 12859895 | doi = 10.1016/S0092-8674(03)00515-4 | s2cid = 1789911 | doi-access = free }}</ref><ref name="pmid15054139">{{cite journal | vauthors = Xu H, Svarovskaia ES, Barr R, Zhang Y, Khan MA, Strebel K, Pathak VK | title = A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 15 | pages = 5652–7 | date = April 2004 | pmid = 15054139 | pmc = 397464 | doi = 10.1073/pnas.0400830101 | bibcode = 2004PNAS..101.5652X | doi-access = free }}</ref> Additionally, amino acids 128–130 on APOBEC3G form a negatively charged motif that is critical for interactions with Vif and the formation of APOBEC3G-Vif complexes. Furthermore, residues 124-127 are important for [[encapsidation]] of APOBEC3G into HIV-1 virions and the resulting antiretroviral activity.<ref name="pmid17267497">{{cite journal | vauthors = Huthoff H, Malim MH | title = Identification of amino acid residues in APOBEC3G required for regulation by human immunodeficiency virus type 1 Vif and Virion encapsidation | journal = Journal of Virology | volume = 81 | issue = 8 | pages = 3807–15 | date = April 2007 | pmid = 17267497 | pmc = 1866099 | doi = 10.1128/JVI.02795-06 }}</ref>

== Mechanism of action ==

APOBEC3G has been widely studied and several mechanisms that negatively affect HIV-1 replication have been identified.

=== Cytidine deamination and hypermutation ===
<!-- Deleted image removed: [[File:Predicted Mechanism of deamination.jpg|thumb|right|upright=1|alt=Potential mechanism| Figure 2: "The mechanism of cytidine deamination by direct [[nucleophilic attack]] at position 4 of the [[pyrimidine]] ring. This mechanism has been proposed for bacterial cytidine deaminase, an enzyme that shows homology to APOBEC1 and activation-induced deaminase (AID) in the vicinity of the nucleotide or Zn2+ binding region.<ref name="Retroviral restriction by APOBEC pr"/>"<ref name="pmid18597677"/> Because APOBEC3G can acts as an AID and is a member of the APOBEC superfamily like APOBEC1, it is likely that a similar mechanism is mediated by APOBEC3G for cytidine deamination.]] -->

APOBEC3G and other proteins in the same family are able to act as [[activation-induced (cytidine) deaminase]]s (AID). APOBEC3G interferes with [[reverse transcription]] by inducing numerous [[deoxycytidine]] to [[deoxyuridine]] mutations in the [[sense (molecular biology)#DNA sense|negative strand]] of the HIV DNA primarily expressed as [[complementary DNA]] (cDNA)<ref name="pmid18499212"/> in a 3'->5'processive manner.<ref name="pmid17428871">{{cite journal | vauthors = Mbisa JL, Barr R, Thomas JA, Vandegraaff N, Dorweiler IJ, Svarovskaia ES, Brown WL, Mansky LM, Gorelick RJ, Harris RS, Engelman A, Pathak VK | display-authors = 6 | title = Human immunodeficiency virus type 1 cDNAs produced in the presence of APOBEC3G exhibit defects in plus-strand DNA transfer and integration | journal = Journal of Virology | volume = 81 | issue = 13 | pages = 7099–110 | date = July 2007 | pmid = 17428871 | pmc = 1933301 | doi = 10.1128/JVI.00272-07 }}</ref> Because APOBEC3G is part of the APOBEC superfamily and acts as an AID, it is likely that the mechanism mediated by APOBEC3G for cytidine deamination is similar to that of an [[E. coli]] cytidine deaminase that is known to be highly homologous to APOBEC1 and AID around the nucleotide and zinc-binding region. The predicted deamination reaction is driven by a direct [[nucleophilic]] attack on position 4 of the cytidine [[pyrimidine]] ring by the zinc-coordinated enzyme. Water is needed as a source of both a proton and [[hydroxyl]] group donor (Figure 2).<ref name="pmid12826402">{{cite journal | vauthors = Neuberger MS, Harris RS, Di Noia J, Petersen-Mahrt SK | title = Immunity through DNA deamination | journal = Trends in Biochemical Sciences | volume = 28 | issue = 6 | pages = 305–12 | date = June 2003 | pmid = 12826402 | doi = 10.1016/S0968-0004(03)00111-7 }}</ref> The deamination (and resulting oxidation) at position 4 yields a carbonyl group and results in a change from cytidine to uridine.{{cn|date=June 2025}}

The deamination activity ultimately results in G→A hypermutations at "hot spots" of the proviral DNA. Such hypermutation ultimately destroys the coding and replicative capacity of the virus, resulting in many nonviable virions.<ref name="pmid18499212"/><ref name="pmid20463080">{{cite journal | vauthors = Sadler HA, Stenglein MD, Harris RS, Mansky LM | title = APOBEC3G contributes to HIV-1 variation through sublethal mutagenesis | journal = Journal of Virology | volume = 84 | issue = 14 | pages = 7396–404 | date = July 2010 | pmid = 20463080 | pmc = 2898230 | doi = 10.1128/JVI.00056-10 }}</ref> APOBEC3G has a much weaker antiviral effect when its active site has been mutated to the point that the protein can no longer mutate retroviral DNA.<ref name="pmid18577210">{{cite journal | vauthors = Goila-Gaur R, Strebel K | title = HIV-1 Vif, APOBEC, and intrinsic immunity | journal = Retrovirology | volume = 5 | issue = 1 | pages = 51 | date = June 2008 | pmid = 18577210 | pmc = 2443170 | doi = 10.1186/1742-4690-5-51 | doi-access = free }}</ref> It was originally thought that the APOBEC3G-mediated deamination can also indirectly lead to viral DNA degradation by DNA repair systems attracted to the mutated residues.<ref name="pmid16971427">{{cite journal | vauthors = Guo F, Cen S, Niu M, Saadatmand J, Kleiman L | title = Inhibition of tRNA₃(Lys)-primed reverse transcription by human APOBEC3G during human immunodeficiency virus type 1 replication | journal = Journal of Virology | volume = 80 | issue = 23 | pages = 11710–22 | date = December 2006 | pmid = 16971427 | pmc = 1642613 | doi = 10.1128/JVI.01038-06 }}</ref> However, this has been discounted because human APOBEC3G reduces viral cDNA levels independently of DNA repair enzymes [[uracil-DNA glycosylase|UNG]] and [[SMUG1]].<ref name="pmid18272574">{{cite journal | vauthors = Langlois MA, Neuberger MS | title = Human APOBEC3G can restrict retroviral infection in avian cells and acts independently of both UNG and SMUG1 | journal = Journal of Virology | volume = 82 | issue = 9 | pages = 4660–4 | date = May 2008 | pmid = 18272574 | pmc = 2293047 | doi = 10.1128/JVI.02469-07 }}</ref>

=== Interference with reverse transcription ===

APOBEC3G interferes with reverse transcription of HIV-1 independent of DNA deamination. [[tRNA]]3Lys typically binds to the HIV-1 [[primer binding site]] to initiate reverse transcription. APOBEC3G can inhibit tRNA3Lys priming, thereby negatively affecting viral ssDNA production and virus infectivity.<ref name="pmid16971427"/> It is predicted that reverse transcription is also negatively affected by APOBEC3G binding to viral RNA and causing steric alterations.<ref name="pmid18789977"/>

=== Interference with viral DNA integration ===

APOBEC3G was associated with interference of viral DNA integration into the host genome in a manner dependent on functional catalytic domains and deaminase activity. Mbisa et al. saw that APOBEC3G interferes with the processing and removal of primer tRNA from the DNA minus strand, thus leading to aberrant viral 3' [[long terminal repeat]] (LTR) DNA ends. These viral DNA ends are inefficient substrates for integration and plus-strand DNA transfer. As a result, HIV-1 provirus formation is inhibited.<ref name="pmid17428871"/>

==Biological function==
=== HIV encapsidation ===
[[File:Mechanisms of encapsidation.png|thumb|left|upright=1|alt=APOBEC3G incorporation into virions | Figure 3: Four proposed mechanisms of APOBEC3G encapsidation in HIV-1 virions. The mechanisms involving interaction with viral RNA and interaction with Gag proteins have been extensively confirmed.<ref name="pmid18597677"/>]]

APOBEC3G mRNA is expressed in certain cells, referred to as non-permissive cells, in which HIV-1 cannot properly infect and replicate in the absence of Vif. Such cells include physiologically relevant primary [[CD4]] [[T lymphocytes]] and [[macrophages]].<ref name="pmid20538015">{{cite journal | vauthors = Wissing S, Galloway NL, Greene WC | title = HIV-1 Vif versus the APOBEC3 cytidine deaminases: an intracellular duel between pathogen and host restriction factors | journal = Molecular Aspects of Medicine | volume = 31 | issue = 5 | pages = 383–97 | date = October 2010 | pmid = 20538015 | pmc = 2967609 | doi = 10.1016/j.mam.2010.06.001 }}</ref> The encapsidation of APOBEC3G into HIV-1 [[virions]] is very important for the spread of APOBEC3G and the exertion of anti-retroviral activity. Encapsidation of APOBEC3G may occur by at least the following four proposed mechanisms (Figure 3): '''1.''' Non-specific packaging of APOBEC3G '''2.''' APOBEC3G interaction with host RNA '''3.''' APOBEC3G interaction with viral RNA '''4.''' Interaction of APOBEC3G with HIV-1 Gag proteins.  Only the latter two mechanisms have been extensively supported.<ref name="pmid18597677">{{cite journal | vauthors = Strebel K, Khan MA | title = APOBEC3G encapsidation into HIV-1 virions: which RNA is it? | journal = Retrovirology | volume = 5 | issue = 55 | pages = 55 | date = July 2008 | pmid = 18597677 | pmc = 2491656 | doi = 10.1186/1742-4690-5-55 | doi-access = free }}</ref>

The amount that is incorporated into virions is dependent on the level of APOBEC3G expression within the cell producing the virion. Xu et al. conducted studies with [[PBMC]] cells and found that, in the absence of Vif, 7±4 APOBEC3G molecules were incorporated into the virions and resulted in potent inhibition of HIV-1 replication.<ref name="pmid17126871">{{cite journal | vauthors = Xu H, Chertova E, Chen J, Ott DE, Roser JD, Hu WS, Pathak VK | title = Stoichiometry of the antiviral protein APOBEC3G in HIV-1 virions | journal = Virology | volume = 360 | issue = 2 | pages = 247–56 | date = April 2007 | pmid = 17126871 | doi = 10.1016/j.virol.2006.10.036 | doi-access = free }}</ref>

In addition to deterring replication of exogenous retroviruses, A3G also acts upon human [[endogenous retrovirus]]es, leaving similar signatures of hypermutations in them.<ref>{{cite journal | vauthors = Armitage AE, Katzourakis A, de Oliveira T, Welch JJ, Belshaw R, Bishop KN, Kramer B, McMichael AJ, Rambaut A, Iversen AK | display-authors = 6 | title = Conserved footprints of APOBEC3G on Hypermutated human immunodeficiency virus type 1 and human endogenous retrovirus HERV-K(HML2) sequences | journal = Journal of Virology | volume = 82 | issue = 17 | pages = 8743–61 | date = September 2008 | pmid = 18562517 | pmc = 2519685 | doi = 10.1128/JVI.00584-08 }}</ref><ref>{{cite journal | vauthors = Lee YN, Malim MH, Bieniasz PD | title = Hypermutation of an ancient human retrovirus by APOBEC3G | journal = Journal of Virology | volume = 82 | issue = 17 | pages = 8762–70 | date = September 2008 | pmid = 18562521 | pmc = 2519637 | doi = 10.1128/JVI.00751-08 }}</ref>

== Disease relevance ==
APOBEC3G is expressed within the non-permissive cells and is a key inhibitory factor of HIV-1 replication and infectivity. However, Vif counteracts this antiretroviral factor, enabling production of viable and infective HIV-1 virions in the presence of APOBEC3G activity .<ref name="pmid20538015"/><ref name="pmid15383144">{{cite journal | vauthors = Goncalves J, Santa-Marta M | title = HIV-1 Vif and APOBEC3G: multiple roads to one goal | journal = Retrovirology | volume = 1 | issue = 28 | pages = 28 | date = September 2004 | pmid = 15383144 | pmc = 521195 | doi = 10.1186/1742-4690-1-28 | doi-access = free }}</ref> In particular, Vif prevents incorporation of APOBEC3G into HIV-1 virions and promotes destruction of the enzyme in a manner independent of all other HIV-1 proteins.<ref name="pmid14527406">{{cite journal | vauthors = Stopak K, de Noronha C, Yonemoto W, Greene WC | title = HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability | journal = Molecular Cell | volume = 12 | issue = 3 | pages = 591–601 | date = September 2003 | pmid = 14527406 | doi = 10.1016/S1097-2765(03)00353-8 | doi-access = free }}</ref>

While APOBEC3G has typically been studied as a vital protein exhibiting potent antiviral effects on HIV-1, recent studies have elucidated the potential of APOBEC3G-mediated mutation to help to facilitate the propagation HIV-1. The number of deaminations in the preferred regions varies from one to many, possibly dependent on the time of exposure to APOBEC3G.<ref name="pmid20463080"/>  Additionally, it has been shown that there is a dose response between intracellular APOBEC3G concentration and degree of viral hypermutation.<ref name="pmid18339206">{{cite journal | vauthors = Pillai SK, Wong JK, Barbour JD | title = Turning up the volume on mutational pressure: is more of a good thing always better? (A case study of HIV-1 Vif and APOBEC3) | journal = Retrovirology | volume = 5 | issue = 26 | pages = 26 | date = March 2008 | pmid = 18339206 | pmc = 2323022 | doi = 10.1186/1742-4690-5-26 | doi-access = free }}</ref> Some HIV-1 [[provirus]]es with APOBEC3G-mediated mutation have been shown to thrive because they carry too few mutations at APOBEC3G hotspots or because recombination between a lethally APOBEC3G-restricted provirus and a viable provirus has occurred.<ref name="pmid18391217">{{cite journal | vauthors = Mulder LC, Harari A, Simon V | title = Cytidine deamination induced HIV-1 drug resistance | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 14 | pages = 5501–6 | date = April 2008 | pmid = 18391217 | pmc = 2291111 | doi = 10.1073/pnas.0710190105 | bibcode = 2008PNAS..105.5501M | doi-access = free }}</ref> Such sublethal mutagenesis contributes to greater [[genetic diversity]] among the HIV-1 virus population, demonstrating the potential for APOBEC3G to enhance HIV-1's ability to adapt and propagate.{{cn|date=June 2025}}

== References ==
{{Reflist|35em}}

== External links ==
* {{UCSC gene info|APOBEC3G}}

== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Prochnow C, Bransteitter R, Klein MG, Goodman MF, Chen XS | title = The APOBEC-2 crystal structure and functional implications for the deaminase AID | journal = Nature | volume = 445 | issue = 7126 | pages = 447–51 | date = January 2007 | pmid = 17187054 | doi = 10.1038/nature05492 | bibcode = 2007Natur.445..447P | s2cid = 4394772 }}
* {{cite journal | vauthors = Iwabu Y, Kinomoto M, Tatsumi M, Fujita H, Shimura M, Tanaka Y, Ishizaka Y, Nolan D, Mallal S, Sata T, Tokunaga K | display-authors = 6 | title = Differential anti-APOBEC3G activity of HIV-1 Vif proteins derived from different subtypes | journal = The Journal of Biological Chemistry | volume = 285 | issue = 46 | pages = 35350–8 | date = November 2010 | pmid = 20833716 | pmc = 2975159 | doi = 10.1074/jbc.M110.173286 | doi-access = free }}
{{refend}}

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[[Category:EC 3.5.4]]
[[Category:HIV/AIDS]]