Distinct combinations of amino acid substitutions in N-terminal domain of Gag-capsid afford HIV-1 resistance to rhesus TRIM5α

Microbes Infect. 2014 Nov;16(11):936-44. doi: 10.1016/j.micinf.2014.08.017. Epub 2014 Sep 4.

Abstract

TRIM5α is a potent anti-retroviral factor that interacts with viral capsid (CA) in a species-specific manner. Recently, we and others reported generation of two distinct HIV-1 CAs that effectively overcome rhesus TRIM5α-imposed species barrier. In this study, to directly compare the effect of different mutations in the two HIV-1 CAs on evasion from macaque TRIM5-restriction, we newly generated macaque-tropic HIV-1 (HIV-1mt) proviral clones carrying the distinct CAs in the same genomic backbone, and examined their replication abilities in macaque TRIM5-overexpressing human cells and in rhesus cells. Comparative analysis of amino acid sequences and homology modeling-based structures revealed that, while both CAs gained some mutated amino acids with similar physicochemical properties, their overall appearances of N-terminal domains were different. Experimentally, the two CAs exhibited incomplete TRIM5α-resistance relative to SIVmac239 CA and different degrees of susceptibility to various TRIM5 proteins. Finally, two HIV-1mt clones carrying a different combination of the CA mutations were found to grow to a comparable extent in established and primary rhesus cells. Our data show that there could be some distinct CA patterns to confer significant TRIM5-resistance on HIV-1.

Keywords: Capsid; Gag-CA; HIV-1; HIV-1mt; Rhesus macaque; TRIM5α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution*
  • Animals
  • Capsid Proteins / genetics
  • Capsid Proteins / metabolism
  • Cell Line
  • HIV Infections / immunology*
  • HIV-1 / physiology*
  • Humans
  • Macaca mulatta
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Proteins / metabolism*
  • Ubiquitin-Protein Ligases
  • Viral Tropism*
  • Virus Replication*
  • gag Gene Products, Human Immunodeficiency Virus / genetics*
  • gag Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • Capsid Proteins
  • Mutant Proteins
  • Proteins
  • gag Gene Products, Human Immunodeficiency Virus
  • TRIM5(alpha) protein, rhesus monkey
  • Ubiquitin-Protein Ligases