Although level of pVL is closely associated with the rate of HIV disease progression, it does not measure disease progression directly. We therefore calculated the rate

of decline in CD4+ T cell counts (see the Materials and Methods), and investigated their association with HLA allele expression as well, but failed to detect any alterations in the rate of decline as the HIV epidemic matured (data not shown). This may be due to the low statistical power of the present study, therefore larger scale studies are warranted in order to determine to what extent, and for which HLA alleles, such accumulations of CTL escape have been occurring, and how they have been affecting disease Apoptosis inhibitor progression. In the present study, we have GSK2126458 in vivo demonstrated that: (1) there are no individual HLA class I alleles which are strongly associated with the level of pVL in the Japanese population at the current time; (2) the Japanese population has a narrow HLA distribution and lacks in the most protective HLA-B27/B57; (3) the proposed advantage of rare class I supertypes and the disadvantage of homozygotes

for Bw6 motif cannot be applied to all ethnic groups across the globe; and (4) HLA-B51 has been losing its dominant effects at the population level over time, whereas this is not the case for the other alleles. Despite substantial numbers of HIV-1 viremia controllers having been recognized in Japan, this population lacks the well-known protective alleles HLA-B27/B57. We therefore expected to discover novel associations between HIV disease progression and HLA class I alleles which are unique to Asian populations. However, in the cross-sectional analysis, we did not identify any significant associations between the level of pVL and expression of individual class I alleles, indicating

that, regardless of the geographical part of the world, the protective effects of HLA alleles are greatly biased to a few of the prominent alleles like HLA-B27/B57. The discordant results for HLA supertypes and homozygosity of the Bw6 motif between Japan and the USA are likely see more also attributable to the lack of HLA-B27/B57 in the Japanese population. These two exceptional alleles are known to have targeting epitopes within Gag protein (10, 30–35). Likewise it has been suggested that expression of HLA alleles other than B27/57, but having targeting epitopes within Gag protein, are associated with lower pVL (8, 36–40). Therefore it is warranted to confirm that Gag specific CTL responses are associated with lower pVL in Japanese people who lack HLA-B27/57. In the cross-sectional analysis, we did not identify significant associations between pVL and HLA-A11, 26, B51 or Cw14 expression, all of which have been shown to be protective in Caucasians (7), However, subsequent analysis revealed that HLA-B51, at least, was protective in the past, indicating that there has been loss of targeting epitopes in the viral strains circulating in this population.