Pressure From Trim5 Alpha Contributes To Control Of Hiv-1 Replication By Individuals Expressing Protective Hla-B Alleles

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 TRIM5 alpha (hTRIM5 alpha) could contribute to viral control. The hTRIM5 alpha 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 hTRIM5 alpha 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 hTRIM5 alpha sensitivity. In HLA-B*27(+) controllers, hTRIM5 alpha sensitivity was associated with a significant reduction in emergence of key CTL mutations. In several patients, viral evolution to avoid hTRIM5 alpha 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, hTRIM5 alpha, 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 hTRIM5 alpha sensitivity or impair viral replicative capacity.