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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.
Highlights
The pathogenesis of human immunodeficiency virus-type 1 (HIV-1) infection correlates with the level of active viral replication and relates to a variety of factors specific to the virus, the host, and its immune system
Cytidine deaminases of the human APOBEC3 gene family act as an intrinsic defense mechanism against infection with HIV-1 and other viruses
Mutations at APOBEC3 editing contexts that occurred at particular positions within specific known or predicted epitopes could disrupt peptide binding critical for immune control
Summary
The pathogenesis of HIV-1 infection correlates with the level of active viral replication and relates to a variety of factors specific to the virus, the host, and its immune system. Nascent HIV-1 cDNA is vulnerable to mutation by host cell single-stranded cytidine deaminases that edit cytidine to uridine in the minus strand DNA copied from the viral RNA genome, giving rise to G-to-A mutation of the plus strand of viral DNA with a graded frequency of deamination from the primer binding site to the central polypurine tract and the central polypurine tract to the 39 polypurine tract regions [5,6,7,8]. Cytidine deaminases of the APOBEC3 gene family have specificity for single-stranded DNA and inhibit infection by a diverse array of RNA and DNA viruses and retrotransposons by interfering with viral genome replication and littering the genome with deleterious mutations [10,11]. Mutations mediated by APOBEC3 molecules have a strong preference for a 59-GG-39 and 59-GA-39 dinucleotide context of the edited sites (target nucleotide underlined) [1,12,13]
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