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Papers In Press, published online ahead of print October 16, 2001
LMM NIAID, NIAID NIH, Bethesda, MD 20892-1576
Corresponding Author: aradhana{at}helix.nih.gov
M-tropic HIV infection of primary human T cells and macrophages requires optimal cell surface expression of the chemokine receptor CCR5 in addition to CD4. Natural mutations of CCR5 that impair surface expression bestow in the homozygous state complete resistance to M-tropic HIV infection. ccr5
J. Biol. Chem, 10.1074/jbc.M108321200
Submitted on August 29, 2001
Revised on October 9, 2001
Accepted on October 15, 2001
Reduced cell surface expression of CCR5 in CCR5
32 heterozygotes is mediated by gene dosage, not by receptor sequestration
32 is the major prototype of such mutants. ccr532 heterozygosity is associated with delayed onset of AIDS and reduced risk of initial transmission, and this correlates with reduced levels of CCR5 and reduced infectability of CD4+ cells. In addition to gene dosage, sequestration of wt CCR5 by mutant protein has been proposed as a mechanism to explain reduced surface expression of CCR5 in cells from ccr532 and CCR5-893(-) heterozygotes. However, here we demonstrate that molar excess of ccr532 or related deletion mutants do not significantly impair the cell surface density of co-expressed wt receptor either in human epithelial cells or Jurkat T cells. Further, ligand dependent signaling and M-tropic HIV usage of wt receptor are also unaffected. Nascent wt receptor does associate with ccr532 and related mutant proteins, and with other unrelated CC and CXC chemokine receptors under transient labeling conditions. However, using confocal microscopy, we demonstrate that in the steady-state, wt and truncated CCR5 proteins segregate into non-overlapping sub-cellular compartments. These findings together with the observed and known variability in the cell surface density of CCR5 on quiescent PBLs lead us to conclude that reduced CCR5 gene dosage rather than receptor sequestration is the major determinant of reduced CCR5 expression in cells from ccr532 heterozygotes.
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