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J. Biol. Chem., Vol. 277, Issue 3, 2287-2301, January 18, 2002

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Reduced Cell Surface Expression of CCR5 in CCR532 Heterozygotes Is Mediated by Gene Dosage, Rather Than by Receptor Sequestration^*

Sundararajan Venkatesan^§, Ana Petrovic, Donald I. Van Ryk, Massimo Locati^¶, Drew Weissman, and Philip M. Murphy^**

From the  Laboratory of Molecular Microbiology and ^** Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892, ^¶ Istituto di Patologia Generale, Via Mangiagalli, Milano, 20133 Italy, and the  Division of Infectious Diseases, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Macrophage tropic (M-tropic) human immunodeficiency virus (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. ccr532 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 wild type (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 a molar excess of ccr532 or related deletion mutants does 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 nonoverlapping subcellular 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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