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TRIM5α Resistance Escape Mutations in the Capsid Are Transferable between Simian Immunodeficiency Virus Strains

Fan Wu1, Andrea Kirmaier2, Ellen White3

  • 1Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA wuf2@niaid.nih.gov vhirsch@niaid.nih.gov.

Journal of Virology
|September 30, 2016
PubMed

Insights

Simian immunodeficiency virus (SIV) capsid mutations can overcome rhesus macaque TRIM5α restriction, improving SIV replication. This advance enables more reliable simian immunodeficiency virus (SIV) studies for human immunodeficiency virus (HIV) vaccine development.

Area of Science:

  • Virology and Immunology
  • Vaccine Development
  • Primate Models

Background:

  • Polymorphisms in TRIM5α (TRIM-cotransporter factor 5 alpha) present a significant barrier in using simian immunodeficiency virus (SIV) for human immunodeficiency virus (HIV) vaccine research in rhesus macaques.
  • Common rhesus macaque TRIM5α alleles restrict SIV acquisition and replication, complicating vaccine efficacy studies.
  • Previous work identified capsid gene variations conferring TRIM5α resistance and improved SIV replication in macaques.

Purpose of the Study:

  • To engineer TRIM5α-resistant simian immunodeficiency virus (SIV) strains without requiring animal passage.
  • To evaluate the efficacy of TRIM5α-resistant SIV variants in rhesus macaques with varying TRIM5α genotypes.
  • To provide a method for generating diverse SIV strains to mitigate TRIM5α restriction in HIV vaccine studies.

Main Methods:

  • Introduction of specific amino acid substitutions into the capsid gene of the SIVsmE660 strain to confer TRIM5α resistance.
  • Generation of TRIM5α-resistant SIV variants in vitro, bypassing the need for animal passage.
  • Infection and replication assessment of a selected SIVsmE660 variant in rhesus macaques possessing both permissive and restrictive TRIM5α alleles.

Main Results:

  • Engineered SIVsmE660 variants demonstrated resistance to TRIM5α restriction in vitro.
  • The SIVsmE660 variant efficiently infected and replicated in rhesus macaques with restrictive TRIM5α genotypes.
  • Replication levels in macaques with restrictive TRIM5α were comparable to those with permissive TRIM5α genotypes.

Conclusions:

  • Mutations within the SIV capsid can effectively confer resistance to TRIM5α restriction without necessitating animal passage.
  • This strategy offers a viable approach to create diverse SIV strains for more robust HIV vaccine evaluations.
  • Overcoming TRIM5α restriction enhances the utility of SIV in rhesus macaque models for advancing HIV vaccine development.

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