Linkage of the CCR5 Delta 32 mutation with a functional polymorphism of CD45RA

A 32-bp deletion in CCR5 (CCR5 Delta 32) confers to PBMC resistance to HIV- 1 isolates that use CCR5 as a coreceptor, To study this mutation in T cell development, we have screened 571 human thymus tissues for the mutation. We identified 72 thymuses (12.6%) that were heterozygous and 2 (0.35%) that w ere homozygous for the CCR5 Delta 32 mutation. We found that thymocyte deve lopment was normal in both CCR5 Delta 32 heterozygous and homozygous thymus es, In 3% of thy-muses we identified a functional polymorphism of CD45RA, i n which cortical and medullary thymocytes failed to down-regulate the 200- and 220-kDa CD45RA isoforms during T cell development. Moreover, we found a n association of this CD45 functional polymorphism in thymuses with the CCR 5 Delta 32 mutation (p = 0.00258). In vitro HIV-1 infection assays with CCR 5-using primary isolates demonstrated that thymocytes with the heterozygous CCR5 Delta 32 mutation produced less p24 than did CCR5 wild-type thymocyte s. However, the functional CD45RA polymorphism did not alter the susceptibi lity of thymocytes to HIV-1 infection. Taken together, these data demonstra te association of the CCR5 Delta 32 mutation with a polymorphism in an as y et unknown gene that is responsible for the ability to down-regulate the ex pression of high m.w. CD45RA isoforms. Although the presence of the CCR5 De lta 32 mutation down-regulates HIV-1 infection of thymocytes, the functiona l CD45RA polymorphism does not alter the susceptibility of thymocytes to HI V-1 infection in vitro.