Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5Δ32

Abstract

Human chemokine receptor 5 (CCR5) functions as a co-receptor for Human immunodeficiency virus (HIV-1) infection. CCR5 is a seven-transmembrane cell surface receptor. Recently, a naturally occurring mutation of CCR5, ccr5Δ32, has been described. A small number of Caucasians are homozygously ccr5Δ32/ccr5Δ32, while a larger number of individuals are heterozygously CCR5/ccr5Δ32. The ccr5Δ32/ccr5Δ32 genotype has been linked to e phenotype that is 'highly' protected from HIV-1 infection. On the other hand, several studies have shown that the CCR5/ccr5Δ32 genotype confers 'relative' protection from AIDS with onset of disease being delayed by 2-4 years. Although it is known that peripheral blood lymphocytes from heterozygous individuals (CCR5/ccr5Δ32) support ex vivo HIV-1 replication at a reduced level compared with CCR5/CCR5 cells, the molecular basis for this observation is unknown. Here we report on events that post-translationally modify CCR5. We show that CCR5 progresses through the endoplasmic reticulum prior to appearing on the cell surface. Mature CCR5 can be post-translationally modified by phosphorylation and/or co-translationally by multimerization. By contrast, mutant ccr5Δ32, although retaining the capacity for multimerization, was incapable of being phosphorylated. ccr5Δ32 heterocomplexes with CCR5, and this interaction retains CCR5 in the endoplasmic reticulum resulting in reduced cell surface expression. Thus, co- expression in cells of ccr5Δ32 with CCR5 produces a trans-inhibition by the former of ability by the latter to support HIV-1 infection. Taken together, our findings suggest CCR5/ccr5Δ32 heterodimerization as a molecular explanation for the delayed onset of AIDS in CCR5/ccr5Δ32 individuals.