APOBEC3D and APOBEC3F Potently Promote HIV-1 Diversification and Evolution in Humanized Mouse Model

Sato, Kei; Takeuchi, Junko; Misawa, Naoko; Izumi, Tatsuro; Kobayashi, Tomoko; Kimura, Yuichi; Iwami, Shingo; Takaori‐Kondo, Akifumi; Hu, Wei; Aihara, Kazuyuki; Ito, Mamoru; An, Dong Sung; Pathak, Vinay K.; Koyanagi, Yoshio

doi:10.1371/journal.ppat.1004453

Cited by 84 publications

(188 citation statements)

References 80 publications

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“…With a lower gene inactivation potential and a high rate of NS substitution generation, our results support that A3F is much more effective than A3G at promoting viral sequence evolution. This is also consistent with previous findings that employed other analysis methods and systems (Ara et al, 2014;Armitage et al, 2012Armitage et al, , 2014Kim et al, 2014;Sato et al, 2014;Wood et al, 2009).…”

Section: A3fsupporting

confidence: 93%

“…This thereby provided us with the ability to directly compare how DNA target specificity impacts gene inactivation and retroviral sequence evolution. This is an issue of particular importance as A3F, more than A3G, has been shown to promote HIV-1 diversification and evolution in vivo (Ara et al, 2014;Armitage et al, 2012Armitage et al, , 2014Kim et al, 2014;Sato et al, 2014;Wood et al, 2009). However, the extent to which this diversification correlates with alterations in gene function had not been assessed until now.…”

Section: A3fmentioning

confidence: 99%

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Comparative analysis of the gene-inactivating potential of retroviral restriction factors APOBEC3F and APOBEC3G

Bélanger

Langlois

2015

Journal of General Virology

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APOBEC3 (A3) proteins are host-encoded restriction factors that inhibit retrovirus infection by mutagenic deamination of cytosines in minus-strand DNA replication intermediates. APOBEC3F (A3F) and APOBEC3G (A3G) are two of the most potent A3 enzymes in humans with each having a different target DNA specificity. A3G prefers to deaminate cytosines preceded by a cytosine (59-CC), whereas A3F preferentially targets cytosines preceded by a thymine (59-TC).Here we performed a detailed comparative analysis of retrovirus-encoded gene sequences edited by A3F and A3G, with the aim of correlating the context and intensity of the mutations with their effects on gene function. Our results revealed that, when there are few (TGG) tryptophan codons in the sequence, both enzymes alter gene function with a similar efficiency when given equal opportunities to deaminate in their preferred target DNA context. In contrast, tryptophan-rich genes are efficiently inactivated in the presence of a low mutational burden, through termination codon generation by A3G but not A3F. Overall, our results clearly demonstrated that the target DNA specificity of an A3 enzyme along with the intensity of the mutational burden and the tryptophan content of the gene being targeted are the factors that have the most forceful influence on whether A3-induced mutations will favour either terminal inactivation or genetic diversification of a retrovirus.

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Section: A3fsupporting

confidence: 93%

Section: A3fmentioning

confidence: 99%

Comparative analysis of the gene-inactivating potential of retroviral restriction factors APOBEC3F and APOBEC3G

Bélanger

Langlois

2015

Journal of General Virology

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“…However, this Vif stretch has also been shown before to be specific for counteracting A3G (17,25,26). Until now, our laboratory and others have attributed the effects of mutating this region to A3G (27,30,31). Our infectivity assays combined with direct evidence of A3H degradation clearly indicate that this Vif stretch is critical for counteracting both A3G and A3H (Fig.…”

Section: Discussionsupporting

confidence: 71%

The Structural Interface between HIV-1 Vif and Human APOBEC3H

Ooms

Letko

Simon

2017

J Virol

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Human APOBEC3H (A3H) is a cytidine deaminase that inhibits HIV-1 replication. To evade this restriction, the HIV-1 Vif protein binds A3H and mediates its proteasomal degradation. To date, little information on the Vif-A3H interface has been available. To decipher how both proteins interact, we first mapped the Vifbinding site on A3H by functionally testing a large set of A3H mutants in singlecycle infectivity and replication assays. Our data show that the two A3H ␣-helixes ␣3 and ␣4 represent the Vif-binding site of A3H. We next used viral adaptation and a set of Vif mutants to identify novel, reciprocal Vif variants that rescued viral infectivity in the presence of two Vif-resistant A3H mutants. These A3H-Vif interaction points were used to generate the first A3H-Vif structure model, which revealed that the A3H helixes ␣3 and ␣4 interact with the Vif ␤-sheet (␤2-␤5). This model is in good agreement with previously reported Vif and A3H amino acids important for interaction. Based on the predicted A3H-Vif interface, we tested additional points of contact, which validated our model. Moreover, these experiments showed that the A3H and A3G binding sites on HIV-1 Vif are largely distinct, with both host proteins interacting with Vif ␤-strand 2. Taken together, this virus-host interface model explains previously reported data and will help to identify novel drug targets to combat HIV-1 infection.IMPORTANCE HIV-1 needs to overcome several intracellular restriction factors in order to replicate efficiently. The human APOBEC3 locus encodes seven proteins, of which A3D, A3F, A3G, and A3H restrict HIV-1. HIV encodes the Vif protein, which binds to the APOBEC3 proteins and leads to their proteasomal degradation. No HIV-1 Vif-APOBEC3 costructure exists to date despite extensive research. We and others previously generated HIV-1 Vif costructure models with A3G and A3F by mapping specific contact points between both proteins. Here, we applied a similar approach to HIV-1 Vif and A3H and successfully generated a Vif-A3H interaction model. Importantly, we find that the HIV-1 Vif-A3H interface is distinct from the Vif-A3G and Vif-A3F interfaces, with a small Vif region being important for recognition of both A3G and A3H. Our Vif-A3H structure model informs on how both proteins interact and could guide toward approaches to block the Vif-A3H interface to target HIV replication.KEYWORDS HIV-1, APOBEC3H, Vif, restriction factor, APOBEC3, A3H, HIV T he human APOBEC3 family consists of seven distinct proteins (A3A to A3H), several of which have potent activity against HIV-1 (1, 2). During infection of the new cell, virion-incorporated APOBEC3 proteins target the process of reverse transcription through directly deaminating the viral single-stranded DNA as well as by deaminaseindependent mechanisms (3-6). In turn, HIV-1 counteracts APOBEC3 restriction by

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“…Further, the identities of APOBEC3 genes other than A3G genes that could significantly contribute to HIV-1 extinction in humanized mice remain an outstanding question. The leading candidates are A3F, APOBEC3H (A3H), and APOBEC3D (A3D), in descending order of likely importance (2,(20)(21)(22). However, evidence for significant nondeaminase activity in vivo has not been forthcoming (22).…”

mentioning

confidence: 99%

APOBEC3G and APOBEC3F Act in Concert To Extinguish HIV-1 Replication

Krisko

Begum

Baker

et al. 2016

J Virol

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The multifunctional HIV-1 accessory protein Vif counters the antiviral activities of APOBEC3G (A3G) and APOBEC3F (A3F), and some Vifs counter stable alleles of APOBEC3H (A3H). Studies in humanized mice have shown that HIV-1 lacking Vif expression is not viable. Here, we look at the relative contributions of the three APOBEC3s to viral extinction. Inoculation of bone marrow/liver/thymus (BLT) mice with CCR5-tropic HIV-1 JRCSF (JRCSF) expressing a vif gene inactive for A3G but not A3F degradation activity (JRCSFvifH42/43D) displayed either no or delayed replication. JRCSF expressing a vif gene mutated to inactivate A3F degradation but not A3G degradation (JRCSFvifW79S) always replicated to high viral loads with variable delays. JRCSF with vif mutated to lack both A3G and A3F degradation activities (JRCSFvifH42/43DW79S) failed to replicate, mimicking JRCSF without Vif expression (JRCSF⌬vif). JRCSF and JRCSFvifH42/43D, but not JRCSFvifW79S or JRCSFvifH42/43DW79S, degraded APOBEC3D. With one exception, JRCSFs expressing mutant Vifs that replicated acquired enforced vif mutations. These mutations partially restored A3G or A3F degradation activity and fully replaced JRCSFvifH42/43D or JRCSFvifW79S by 10 weeks. Surprisingly, induced mutations temporally lagged behind high levels of virus in blood. In the exceptional case, JRCSFvifH42/ 43D replicated after a prolonged delay with no mutations in vif but instead a V27I mutation in the RNase H coding sequence. JRCSFvifH42/43D infections exhibited massive GG/AG mutations in pol viral DNA, but in viral RNA, there were no fixed mutations in the Gag or reverse transcriptase coding sequence. A3H did not contribute to viral extinction but, in combination with A3F, could delay JRCSF replication. A3H was also found to hypermutate viral DNA. IMPORTANCEVif degradation of A3G and A3F enhances viral fitness, as virus with even a partially restored capacity for degradation outgrows JRCSFvifH42/43D and JRCSFvifW79S. Unexpectedly, fixation of mutations that replaced H42/43D or W79S in viral RNA lagged behind the appearance of high viral loads. In one exceptional JRCSFvifH42/43D infection, vif was unchanged but replication proceeded after a long delay. These results suggest that Vif binds and inhibits the non-cytosine deaminase activities of intact A3G and intact A3F, allowing JRCSFvifH42/43D and JRCSFvifW79S to replicate with reduced fitness. Subsequently, enhanced Vif function is acquired by enforced mutations. In infected cells, JRCSF⌬vif and JRCSFvifH42/43DW79S are exposed to active A3F and A3G and fail to replicate. JRCSFvifH42/43D Vif degrades A3F and, in some cases, overcomes A3G mutagenic activity to replicate. Vif may have evolved to inhibit A3F and A3G by stoichiometric binding and subsequently acquired the ability to target these proteins to proteasomes.

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APOBEC3D and APOBEC3F Potently Promote HIV-1 Diversification and Evolution in Humanized Mouse Model

Cited by 84 publications

References 80 publications

Comparative analysis of the gene-inactivating potential of retroviral restriction factors APOBEC3F and APOBEC3G

Comparative analysis of the gene-inactivating potential of retroviral restriction factors APOBEC3F and APOBEC3G

The Structural Interface between HIV-1 Vif and Human APOBEC3H

APOBEC3G and APOBEC3F Act in Concert To Extinguish HIV-1 Replication

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