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 were homozygous for the CCR5 Delta 32 mutation. We found that thymocyte development was normal in both CCR5 Delta 32 heterozygous and homozygous thymuses. In 3% of thymuses we identified a functional polymorphism of CD45RA, in which cortical and medullary thymocytes failed to down-regulate the 200- and 220-kDa CD45RA isoforms during T cell development. Moreover, we found an association of this CD45 functional polymorphism in thymuses with the CCR5 Delta 32 mutation (p = 0.00258). In vitro HIV-1 infection assays with CCR5-using primary isolates demonstrated that thymocytes with the heterozygous CCR5 Delta 32 mutation produced less p24 than did CCR5 wild-type thymocytes. However, the functional CD45RA polymorphism did not alter the susceptibility of thymocytes to HIV-1 infection. Taken together, these data demonstrate association of the CCR5 Delta 32 mutation with a polymorphism in an as yet unknown gene that is responsible for the ability to down-regulate the expression of high m.w. CD45RA isoforms. Although the presence of the CCR5 Delta 32 mutation down-regulates HIV-1 infection of thymocytes, the functional CD45RA polymorphism does not alter the susceptibility of thymocytes to HIV-1 infection in vitro.
Liao
H X
HX
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. hliao@duke.edu'
Montefiori
D C
DC
Patel
D D
DD
Lee
D M
DM
Scott
W K
WK
Pericak-Vance
M
M
Haynes
B F
BF
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D008040:Genetic Linkage; D015658:HIV Infections / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008875:Middle Aged; D009154:Mutation; D009924:Organ Culture Techniques; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D019713:Receptors, CCR5; D017493:Leukocyte Common Antigens