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PLoS Pathog. 2014 Jul 31;10(7):e1004281. doi: 10.1371/journal.ppat.1004281. eCollection 2014 Jul.

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

Author information

1
Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
2
Division of Infectious Diseases, University of California San Diego, San Diego, California, United States of America.
3
Department of Infectious Diseases, King's College London, Guy's Hospital, London, United Kingdom.
4
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
5
Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
6
Division of Infectious Diseases, University of California San Diego, San Diego, California, United States of America; Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America.
7
Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America; Santa Fe Institute, Santa Fe, New Mexico, 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.

PMID:
25080100
PMCID:
PMC4117599
DOI:
10.1371/journal.ppat.1004281
[Indexed for MEDLINE]
Free PMC Article

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