TRIM5 alpha drives SIVsmm evolution in rhesus macaques.

Area of Science:

• Virology
• Immunology
• Evolutionary Biology

Background:

• Host restriction factors, like TRIM5α, are key drivers of viral evolution.
• TRIM5α polymorphisms significantly influence simian immunodeficiency virus (SIV) replication in macaques.
• Previous work identified TRIM5α allele variations affecting SIVsmm viremia levels.

Purpose of the Study:

• To investigate how SIV overcomes TRIM5α restriction.
• To identify specific viral adaptations enabling escape from TRIM5α-mediated innate immunity.
• To understand the role of TRIM5α in primate lentivirus cross-species transmission.

Main Methods:

• Utilized a rhesus macaque model with defined TRIM5α genotypes (TRIM5(Q), TRIM5(TFP/TFP), TRIM5(Cyp/TFP)).
• Analyzed SIVsmm viremia dynamics and identified specific amino acid substitutions in the viral capsid.
• Introduced identified mutations into SIVsmE543 clone for in vitro and in vivo fitness assessments.

Main Results:

• SIVsmm initially restricted by TRIM5α eventually overcomes this barrier via capsid mutations.
• Specific capsid mutations (P37S, R98S) confer escape from TRIM5(TFP) restriction.
• CypA binding-loop mutations (GPLPA87-91) enable escape from TRIM5(Cyp) restriction; P37S/R98S enhance in vivo fitness.

Conclusions:

• TRIM5α acts as a significant selective pressure on SIV evolution and adaptation in primates.
• Viral capsid adaptations are crucial for overcoming TRIM5α-mediated restriction.
• Identified mutations provide direct evidence for TRIM5α's role in shaping SIV transmission dynamics.