title: Pressure from TRIM5α contributes to control of HIV-1 replication by individuals expressing protective HLA-B alleles.
abstract: The expression of certain HLA class I alleles, including HLA-B*27 and HLA-B*57, is associated with better control of human immunodeficiency virus type 1 (HIV-1) infection, but the mechanisms responsible are not fully understood. We sought evidence that pressure from the human restriction factor TRIM5α (hTRIM5α) could contribute to viral control. The hTRIM5α sensitivity of viruses from both HLA-B*57-positive (HLA-B*57(+)) and HLA-B*27(+) patients who spontaneously controlled viral replication, but not viruses from viremic patients expressing these alleles, was significantly greater than that of viruses from patients not expressing these protective HLA-B alleles. Overall, a significant negative correlation between hTRIM5α sensitivity and viral load was observed. In HLA-B*57(+) patients, the T242N mutation in the HLA-B*57-restricted TW10 CD8(+) T lymphocyte (CTL) epitope was strongly associated with hTRIM5α sensitivity. In HLA-B*27(+) controllers, hTRIM5α sensitivity was associated with a significant reduction in emergence of key CTL mutations. In several patients, viral evolution to avoid hTRIM5α sensitivity was observed but could be associated with reduced viral replicative capacity. Thus, in individuals expressing protective HLA-B alleles, the combined pressures exerted by CTL, hTRIM5α, and capsid structural constraints can prevent viral escape both by impeding the selection of necessary resistance/compensatory mutations and forcing the selection of escape mutations that increase hTRIM5α sensitivity or impair viral replicative capacity.
authors.affiliation: INSERM U941, Paris, France.
authors.forename: Clémence
authors.initials: C
authors.lastname: Granier
authors.forename: Emilie
authors.initials: E
authors.lastname: Battivelli
authors.forename: Camille
authors.initials: C
authors.lastname: Lécuroux
authors.forename: Alain
authors.initials: A
authors.lastname: Venet
authors.forename: Olivier
authors.initials: O
authors.lastname: Lambotte
authors.forename: Marion
authors.initials: M
authors.lastname: Schmitt-Boulanger
authors.forename: Constance
authors.initials: C
authors.lastname: Delaugerre
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Molina
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Chakrabarti
authors.forename: François
authors.initials: F
authors.lastname: Clavel
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Hance
mesh_terms: D000328:Adult; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D019562:Viral Load
chemical_list: D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; C090660:HLA-B protein, human; D015796:HLA-B27 Antigen; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases