The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type T infection

The inflammatory disease human T cell lymphotropic virus type I (HTLV-I)-as sociated myelopathy (HAM/TSP) occurs in only 1-2% of HTLV-I-infected indivi duals and is associated with a high provirus load of HTLV-I, We hypothesize that a person's risk of developing HAM/TSP depends upon the efficiency of their immune response to the virus, which differs between individuals becau se of polymorphism in genes that influence this response. Previously we sho wed that the possession of HLA-A*02 was associated with a lower risk of HAM /TSP, and with a lower provirus load in healthy carriers of HTLV-I. However , HLA-A*02 did not account for all the observed difference in the risk of H AM/TSP, Here we present evidence, in the same study population in Japan, th at HLA-Cw*08 was also associated with disease protection (probability value , two-tailed test = 0.002) and with a lower proviral load in healthy carrie rs. Possession of the A*02 and/or Cw*08 genes prevented 36% of potential HA M/TSP cases. In contrast, HLA-B*5401 was associated with a higher susceptib ility to HAM/TSP (probability value, two-tailed test = 0.0003) and with a h igher provirus load in HAM/TSP patients. At a given provirus load, B*5401 a ppeared to increase the risk of disease. The fraction of HAM/TSP cases attr ibutable to B*5401 was 17%, Furthermore, individuals who were heterozygous at all three HLA class I loci have a lower HTLV-I provirus load than those who were homozygous at one or more loci. These results are consistent with the proposal that a strong class I-restricted CTL response to HTLV-I reduce s the proposal load and hence the risk of disease.