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Human APOBEC3 induced mutation of human immunodeficiency virus type-1 contributes to adaptation and evolution in natural infection.

Kim EY, Lorenzo-Redondo R, Little SJ, Chung YS, Phalora PK, Maljkovic Berry I, Archer J, Penugonda S, Fischer W, Richman DD, Bhattacharya T, Malim MH, Wolinsky SM - PLoS Pathog. (2014)

Bottom Line: Human APOBEC3 proteins have additionally been proposed to induce infrequent, potentially non-lethal G-to-A mutations that make subtle contributions to sequence diversification of the viral genome and adaptation though acquisition of beneficial mutations.Viral substitutions were highest in the preferred trinucleotide contexts of the edited sites for the APOBEC3 deaminases.Consistent with the effects of immune selection, amino acid changes accumulated at the APOBEC3 editing contexts located within human leukocyte antigen (HLA)-appropriate epitopes that are known or predicted to enable peptide binding.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.

ABSTRACT
Human APOBEC3 proteins are cytidine deaminases that contribute broadly to innate immunity through the control of exogenous retrovirus replication and endogenous retroelement retrotransposition. As an intrinsic antiretroviral defense mechanism, APOBEC3 proteins induce extensive guanosine-to-adenosine (G-to-A) mutagenesis and inhibit synthesis of nascent human immunodeficiency virus-type 1 (HIV-1) cDNA. Human APOBEC3 proteins have additionally been proposed to induce infrequent, potentially non-lethal G-to-A mutations that make subtle contributions to sequence diversification of the viral genome and adaptation though acquisition of beneficial mutations. Using single-cycle HIV-1 infections in culture and highly parallel DNA sequencing, we defined trinucleotide contexts of the edited sites for APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H. We then compared these APOBEC3 editing contexts with the patterns of G-to-A mutations in HIV-1 DNA in cells obtained sequentially from ten patients with primary HIV-1 infection. Viral substitutions were highest in the preferred trinucleotide contexts of the edited sites for the APOBEC3 deaminases. Consistent with the effects of immune selection, amino acid changes accumulated at the APOBEC3 editing contexts located within human leukocyte antigen (HLA)-appropriate epitopes that are known or predicted to enable peptide binding. Thus, APOBEC3 activity may induce mutations that influence the genetic diversity and adaptation of the HIV-1 population in natural infection.

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Positions of G-to-A mutations within the APOBEC3 trinucleotide context of the edited sites are shown in the HIV-1 genome.A heat map of the slope of the logistic regression of deamination frequency with increasing amount of APOBEC3 protein expression is shown at left (Spearman correlation coefficient, P<0.05) (A). The nucleic acid position in HXB2 (GenBank Accession number K03455) is to the right of the G-to-A position. A heat map of G-to-A frequency in APOBEC3 trinucleotide context of the edited sites with increasing amounts of expression of each APOBEC3 protein is shown in the middle panel. The location of the guanosine in the trinucleotide context of the edited sites in the segment of the targeted sequence is shown at right. Mutation frequency comparison with and without guanosines within the defined APOBEC3 trinucleotide context of the edited sites per each enzyme is shown (B). Upon removal of guanosine in the APOBEC3 trinucleotide context of the edited sites, substitution rate lowered to 9.77×10−4 mutations per nucleotide substitution.
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ppat-1004281-g002: Positions of G-to-A mutations within the APOBEC3 trinucleotide context of the edited sites are shown in the HIV-1 genome.A heat map of the slope of the logistic regression of deamination frequency with increasing amount of APOBEC3 protein expression is shown at left (Spearman correlation coefficient, P<0.05) (A). The nucleic acid position in HXB2 (GenBank Accession number K03455) is to the right of the G-to-A position. A heat map of G-to-A frequency in APOBEC3 trinucleotide context of the edited sites with increasing amounts of expression of each APOBEC3 protein is shown in the middle panel. The location of the guanosine in the trinucleotide context of the edited sites in the segment of the targeted sequence is shown at right. Mutation frequency comparison with and without guanosines within the defined APOBEC3 trinucleotide context of the edited sites per each enzyme is shown (B). Upon removal of guanosine in the APOBEC3 trinucleotide context of the edited sites, substitution rate lowered to 9.77×10−4 mutations per nucleotide substitution.

Mentions: Using these results, we identified G-to-A mutations in plus strand DNA as a genetic signature to identify a posteriori APOBEC3 nucleotide contexts of the edited sites. Each G-to-A mutation was considered independently (Figure 1C). Because there is about a two-fold increase in the frequency of adenosine relative to guanosine in the viral genome, we corrected for a bias in the 5′-GpA-3′ and 5′-GpG-3′ context raw numbers. For each of the four human APOBEC3 proteins that are the cellular targets for the HIV-1 protein Vif, we identified positions in the Gag gene region of HIV-1 we sequenced where the site-specific G-to-A substitution frequency increased significantly with increasing APOBEC3 protein abundance (Spearman P<0.05; Figure 2A).


Human APOBEC3 induced mutation of human immunodeficiency virus type-1 contributes to adaptation and evolution in natural infection.

Kim EY, Lorenzo-Redondo R, Little SJ, Chung YS, Phalora PK, Maljkovic Berry I, Archer J, Penugonda S, Fischer W, Richman DD, Bhattacharya T, Malim MH, Wolinsky SM - PLoS Pathog. (2014)

Positions of G-to-A mutations within the APOBEC3 trinucleotide context of the edited sites are shown in the HIV-1 genome.A heat map of the slope of the logistic regression of deamination frequency with increasing amount of APOBEC3 protein expression is shown at left (Spearman correlation coefficient, P<0.05) (A). The nucleic acid position in HXB2 (GenBank Accession number K03455) is to the right of the G-to-A position. A heat map of G-to-A frequency in APOBEC3 trinucleotide context of the edited sites with increasing amounts of expression of each APOBEC3 protein is shown in the middle panel. The location of the guanosine in the trinucleotide context of the edited sites in the segment of the targeted sequence is shown at right. Mutation frequency comparison with and without guanosines within the defined APOBEC3 trinucleotide context of the edited sites per each enzyme is shown (B). Upon removal of guanosine in the APOBEC3 trinucleotide context of the edited sites, substitution rate lowered to 9.77×10−4 mutations per nucleotide substitution.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4117599&req=5

ppat-1004281-g002: Positions of G-to-A mutations within the APOBEC3 trinucleotide context of the edited sites are shown in the HIV-1 genome.A heat map of the slope of the logistic regression of deamination frequency with increasing amount of APOBEC3 protein expression is shown at left (Spearman correlation coefficient, P<0.05) (A). The nucleic acid position in HXB2 (GenBank Accession number K03455) is to the right of the G-to-A position. A heat map of G-to-A frequency in APOBEC3 trinucleotide context of the edited sites with increasing amounts of expression of each APOBEC3 protein is shown in the middle panel. The location of the guanosine in the trinucleotide context of the edited sites in the segment of the targeted sequence is shown at right. Mutation frequency comparison with and without guanosines within the defined APOBEC3 trinucleotide context of the edited sites per each enzyme is shown (B). Upon removal of guanosine in the APOBEC3 trinucleotide context of the edited sites, substitution rate lowered to 9.77×10−4 mutations per nucleotide substitution.
Mentions: Using these results, we identified G-to-A mutations in plus strand DNA as a genetic signature to identify a posteriori APOBEC3 nucleotide contexts of the edited sites. Each G-to-A mutation was considered independently (Figure 1C). Because there is about a two-fold increase in the frequency of adenosine relative to guanosine in the viral genome, we corrected for a bias in the 5′-GpA-3′ and 5′-GpG-3′ context raw numbers. For each of the four human APOBEC3 proteins that are the cellular targets for the HIV-1 protein Vif, we identified positions in the Gag gene region of HIV-1 we sequenced where the site-specific G-to-A substitution frequency increased significantly with increasing APOBEC3 protein abundance (Spearman P<0.05; Figure 2A).

Bottom Line: Human APOBEC3 proteins have additionally been proposed to induce infrequent, potentially non-lethal G-to-A mutations that make subtle contributions to sequence diversification of the viral genome and adaptation though acquisition of beneficial mutations.Viral substitutions were highest in the preferred trinucleotide contexts of the edited sites for the APOBEC3 deaminases.Consistent with the effects of immune selection, amino acid changes accumulated at the APOBEC3 editing contexts located within human leukocyte antigen (HLA)-appropriate epitopes that are known or predicted to enable peptide binding.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.

ABSTRACT
Human APOBEC3 proteins are cytidine deaminases that contribute broadly to innate immunity through the control of exogenous retrovirus replication and endogenous retroelement retrotransposition. As an intrinsic antiretroviral defense mechanism, APOBEC3 proteins induce extensive guanosine-to-adenosine (G-to-A) mutagenesis and inhibit synthesis of nascent human immunodeficiency virus-type 1 (HIV-1) cDNA. Human APOBEC3 proteins have additionally been proposed to induce infrequent, potentially non-lethal G-to-A mutations that make subtle contributions to sequence diversification of the viral genome and adaptation though acquisition of beneficial mutations. Using single-cycle HIV-1 infections in culture and highly parallel DNA sequencing, we defined trinucleotide contexts of the edited sites for APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H. We then compared these APOBEC3 editing contexts with the patterns of G-to-A mutations in HIV-1 DNA in cells obtained sequentially from ten patients with primary HIV-1 infection. Viral substitutions were highest in the preferred trinucleotide contexts of the edited sites for the APOBEC3 deaminases. Consistent with the effects of immune selection, amino acid changes accumulated at the APOBEC3 editing contexts located within human leukocyte antigen (HLA)-appropriate epitopes that are known or predicted to enable peptide binding. Thus, APOBEC3 activity may induce mutations that influence the genetic diversity and adaptation of the HIV-1 population in natural infection.

Show MeSH
Related in: MedlinePlus