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Human APOBEC3 Induced Mutation of Human Immunodeficiency Virus Type-1 Contributes to Adaptation and Evolution in Natural Infection
Cytidine deaminases of the human APOBEC3 gene family act as an intrinsic defense mechanism against infection with HIV-1 and other viruses. The APOBEC3 proteins introduce mutations into the viral genome by inducing enzymatic modification of nucleotide sequences and inhibiting synthesis of cDNA strands from the viral RNA. Viral Vif counters this impediment to the fidelity of HIV-1 replication by targeting the APOBEC3 proteins for degradation. Low-level APOBEC3 activity that outlasts blockade by viral Vif may foster infrequent mutations that provide a source of genetic variation upon which natural selection acts. Here, we defined the APOBEC3 nucleotide contexts of the edited sites by titration of the wild type and non-editing APOBEC3 mutant in cultured cells. We then followed the patterns of G-to-A mutations we identified in viral DNA in cells obtained from ten patients with acute infection. Our deep sequencing analyses demonstrate an association between sub-lethal APOBEC3 editing and HIV-1 diversification. Mutations at APOBEC3 editing contexts that occurred at particular positions within specific known or predicted epitopes could disrupt peptide binding critical for immune control. Our findings reveal a role for human APOBEC3 in HIV-1 sequence diversification that may influence fitness and evolution of beneficial variants and phenotypes in the population.
Vyšlo v časopise: Human APOBEC3 Induced Mutation of Human Immunodeficiency Virus Type-1 Contributes to Adaptation and Evolution in Natural Infection. PLoS Pathog 10(7): e32767. doi:10.1371/journal.ppat.1004281
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004281Souhrn
Cytidine deaminases of the human APOBEC3 gene family act as an intrinsic defense mechanism against infection with HIV-1 and other viruses. The APOBEC3 proteins introduce mutations into the viral genome by inducing enzymatic modification of nucleotide sequences and inhibiting synthesis of cDNA strands from the viral RNA. Viral Vif counters this impediment to the fidelity of HIV-1 replication by targeting the APOBEC3 proteins for degradation. Low-level APOBEC3 activity that outlasts blockade by viral Vif may foster infrequent mutations that provide a source of genetic variation upon which natural selection acts. Here, we defined the APOBEC3 nucleotide contexts of the edited sites by titration of the wild type and non-editing APOBEC3 mutant in cultured cells. We then followed the patterns of G-to-A mutations we identified in viral DNA in cells obtained from ten patients with acute infection. Our deep sequencing analyses demonstrate an association between sub-lethal APOBEC3 editing and HIV-1 diversification. Mutations at APOBEC3 editing contexts that occurred at particular positions within specific known or predicted epitopes could disrupt peptide binding critical for immune control. Our findings reveal a role for human APOBEC3 in HIV-1 sequence diversification that may influence fitness and evolution of beneficial variants and phenotypes in the population.
Zdroje
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