TRIM5 alpha Drives SIVsmm Evolution in Rhesus Macaques

PLoS Pathogens

Andrea Kirmaier¹  Welkin Johnson¹  Laura Hall¹  Jennifer S. Morgan¹  Vanessa M. Hirsch²  Ronald Plishka²  Keiko Tomioka²  Robert Goeken²  Sonya Whitted²  Fan Wu²  Kenta Matsuda²  Alicia Buckler-White²  Ilnour Ourmanov² 

[1] Biology Department, Boston College, Chestnut Hill, Massachusetts, United States of America;Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: Macaque;    Viral packaging;    SIV;    Rhesus monkeys;    Viral replication;    Cloning;    Primates;    Amino acid substitution;   

DOI  :  10.1371/journal.ppat.1003577

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The antagonistic interaction with host restriction proteins is a major driver of evolutionary change for viruses. We previously reported that polymorphisms of the TRIM5α B30.2/SPRY domain impacted the level of SIVsmm viremia in rhesus macaques. Viremia in macaques homozygous for the non-restrictive TRIM5α allele TRIM5Q was significantly higher than in macaques expressing two restrictive TRIM5alpha alleles TRIM5TFP/TFP or TRIM5Cyp/TFP. Using this model, we observed that despite an early impact on viremia, SIVsmm overcame TRIM5α restriction at later stages of infection and that increasing viremia was associated with specific amino acid substitutions in capsid. Two amino acid substitutions (P37S and R98S) in the capsid region were associated with escape from TRIM5TFP restriction and substitutions in the CypA binding-loop (GPLPA87-91) in capsid were associated with escape from TRIM5Cyp. Introduction of these mutations into the original SIVsmE543 clone not only resulted in escape from TRIM5α restriction in vitro but the P37S and R98S substitutions improved virus fitness in macaques with homozygous restrictive TRIMTFP alleles in vivo. Similar substitutions were observed in other SIVsmm strains following transmission and passage in macaques, collectively providing direct evidence that TRIM5α exerts selective pressure on the cross-species transmission of SIV in primates.

【 授权许可】

CC BY