title: CCR5Delta32 protein expression and stability are critical for resistance to human immunodeficiency virus type 1 in vivo.
abstract: Human immunodeficiency virus type 1 (HIV-1) infection of individuals carrying the two alleles of the CCR5Delta32 mutation (CCR5(-/-)) has rarely been reported, but how the virus overcomes the CCR5Delta32 protective effect in these cases has not been delineated. We have investigated this in 6 infected (HIV(+)) and 25 HIV(-) CCR5(-/-) individuals. CD4(+) T lymphocytes isolated from HIV(-) CCR5(-/-) peripheral blood mononuclear cells (PBMCs) showed lower levels of CXCR4 expression that correlated with lower X4 Env-mediated fusion. Endogenous CCR5Delta32 protein was detected in all HIV(-) CCR5(-/-) PBMC samples (n = 25) but not in four of six unrelated HIV(+) CCR5(-/-) PBMC samples. Low levels were detected in another two HIV(+) CCR5(-/-) PBMC samples. The expression of adenovirus 5 (Ad5)-encoded CCR5Delta32 protein restored the protective effect in PBMCs from three HIV(+) CCR5(-/-) individuals but failed to restore the protective effect in PBMCs isolated from another three HIV(+) CCR5(-/-) individuals. In the latter samples, pulse-chase analyses demonstrated the disappearance of endogenous Ad5-encoded CCR5Delta32 protein and the accumulation of Ad5-encoded CCR5 during the chase periods. PBMCs isolated from CCR5(-/-) individuals showed resistance to primary X4 but were readily infected by a lab-adapted X4 strain. Low levels of Ad5-encoded CCR5Delta32 protein conferred resistance to primary X4 but not to lab-adapted X4 virus. These data provide strong support for the hypothesis that the CCR5Delta32 protein actively confers resistance to HIV-1 in vivo and suggest that the loss or reduction of CCR5Delta32 protein expression may account for HIV-1 infection of CCR5(-/-) individuals. The results also suggest that other cellular or virally induced factors may be involved in the stability of CCR5Delta32 protein.
authors.affiliation: Indiana University School of Medicine, Department of Microbiology and Immunology, 635 Barnhill Drive, Room 420, Indianapolis, IN 46202, USA.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Agrawal
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Jin
authors.forename: Jeff
authors.initials: J
authors.lastname: Altenburg
authors.forename: L
authors.initials: L
authors.lastname: Meyer
authors.forename: R
authors.initials: R
authors.lastname: Tubiana
authors.forename: Ioannis
authors.initials: I
authors.lastname: Theodorou
authors.forename: Ghalib
authors.initials: G
authors.lastname: Alkhatib
mesh_terms: D000483:Alleles; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D015658:HIV Infections; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D015686:Gene Products, env; D019713:Receptors, CCR5; D019718:Receptors, CXCR4