Open AccessTRIM5 alpha Drives SIVsmm Evolution in Rhesus Macaques
Author(s) -
Fan Wu,
Andrea Kirmaier,
Robert M. Goeken,
Ilnour Ourmanov,
Laurie R. Hall,
Jennifer Morgan,
Kenta Matsuda,
Alicia Buckler-White,
Keiko Tomioka,
Ronald J. Plishka,
Sonya Whitted,
Welkin E. Johnson,
Vanessa M. Hirsch
Publication year - 2013
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1003577
Subject(s) - viremia , capsid , biology , genetics , virology , allele , virus , gene
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 TRIM5 Q was significantly higher than in macaques expressing two restrictive TRIM5alpha alleles TRIM5 TFP/TFP or TRIM5 Cyp/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 TRIM5 TFP restriction and substitutions in the CypA binding-loop (GPLPA87-91) in capsid were associated with escape from TRIM5 Cyp . 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 TRIM TFP 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.