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

Bélanger, Kasandra; Langlois, Marc‐André

doi:10.1099/vir.0.000214

Cited by 9 publications

(13 citation statements)

References 45 publications

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“…A3G mutation of GG to AG is effective in inactivating virus prior to integration, and A3F's GA-to-AA mutations are fewer and relatively ineffective (61). Thus, it seems unlikely that GA-to-AA mutation plays a decisive role in the equivalent susceptibilities of JRCSFvif42/43DW79S and JRCSF⌬vif to extinction.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Low levels of mutations or missense mutations may result in either HIV-1 evolution or have a neutral effect, rather than HIV-1 inactivation [16, 42, 67, 68, 69, 70, 71]. Studies have demonstrated that due to the A3G preferred deamination motif, A3G-induced mutagenesis is likely to induce viral inactivation [50, 64, 66, 72, 73, 74]. However, the A3s that cause 5′GA → 5′AA mutations (A3F, A3H, and A3C) may be more likely to induce HIV-1 genetic diversity and evolution [17, 64, 74].…”

Section: Introductionmentioning

confidence: 99%

“…Studies have demonstrated that due to the A3G preferred deamination motif, A3G-induced mutagenesis is likely to induce viral inactivation [50, 64, 66, 72, 73, 74]. However, the A3s that cause 5′GA → 5′AA mutations (A3F, A3H, and A3C) may be more likely to induce HIV-1 genetic diversity and evolution [17, 64, 74]. These data in combination with data demonstrating that during chronic HIV-1 infection Vif can acquire mutations that partially decrease its ability to induce A3 degradation suggest that HIV-1 can manipulate A3 activity like a mutational rheostat [44, 45, 68].…”

Section: Introductionmentioning

confidence: 99%

Role of co-expressed APOBEC3F and APOBEC3G in inducing HIV-1 drug resistance

Mohammadzadeh

Love

Gibson

et al. 2019

Heliyon

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The APOBEC3 enzymes can induce mutagenesis of HIV-1 proviral DNA through the deamination of cytosine. HIV-1 overcomes this restriction through the viral protein Vif that induces APOBEC3 proteasomal degradation. Within this dynamic host-pathogen relationship, the APOBEC3 enzymes have been found to be beneficial, neutral, or detrimental to HIV-1 biology. Here, we assessed the ability of co-expressed APOBEC3F and APOBEC3G to induce HIV-1 resistance to antiviral drugs. We found that co-expression of APOBEC3F and APOBEC3G enabled partial resistance of APOBEC3F to Vif-mediated degradation with a corresponding increase in APOBEC3F-induced deaminations in the presence of Vif, in addition to APOBEC3G-induced deaminations. We recovered HIV-1 drug resistant variants resulting from APOBEC3-induced mutagenesis, but these variants were less able to replicate than drug resistant viruses derived from RT-induced mutations alone. The data support a model in which APOBEC3 enzymes cooperate to restrict HIV-1, promoting viral inactivation over evolution to drug resistance.

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“…Among the four APOBEC3 members containing double CD domains, A3F and A3G show potent anti-HIV activities 25; 26; 27; 28; 29; 30 , which is through incorporation/encapsidation of the APOBEC3 enzymes into HIV virions 31; 32; 33; 34 . The incorporation/encapsidation into HIV virions, which is mainly mediated through RNA binding by the A3 proteins, requires both CD1 and CD2 domains of A3F, whereas only CD1 of A3G is needed 32; 34; 35; 36; 37; 38; 39 .…”

mentioning

confidence: 99%

The in vitro Biochemical Characterization of an HIV-1 Restriction Factor APOBEC3F: Importance of Loop 7 on Both CD1 and CD2 for DNA Binding and Deamination

Chen

Xiao

Wolfe

et al. 2016

Journal of Molecular Biology

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APOBEC3F (A3F) is a member of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) family of proteins that can deaminate cytosine (C) to uracil (U) on nucleic acids. A3F is one of the four APOBEC members with two Zn-coordinated homologous cytosine deaminase domains (CD), with the others being A3G, A3D, and A3B. Here we report the in vitro characterization of DNA binding and deaminase activities using purified wild type (wt) and various mutant proteins of A3F from an E. coli expression system. We show that, even though CD1 is catalytically inactive and CD2 is the active deaminase domain, presence of CD1 on the N-terminus of CD2 enhances the deaminase activity by over an order of magnitude. This enhancement of CD2 catalytic activity is mainly through the increase of substrate ssDNA binding by the N-terminal CD1 domain. We further show that the loop 7 of both CD1 and CD2 of A3F plays an important role for ssDNA binding for each individual domain, as well as for the deaminase activity of CD2 domain in the full length A3F.

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

Cited by 9 publications

References 45 publications

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

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

Role of co-expressed APOBEC3F and APOBEC3G in inducing HIV-1 drug resistance

The in vitro Biochemical Characterization of an HIV-1 Restriction Factor APOBEC3F: Importance of Loop 7 on Both CD1 and CD2 for DNA Binding and Deamination

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