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CCR532 Protein Expression and Stability Are Critical for Resistance to Human Immunodeficiency Virus Type 1 In Vivo

Lokesh Agrawal,^1, Qingwen Jin,^2, Jeff Altenburg,¹ L. Meyer,³ R. Tubiana,⁴ Ioannis Theodorou,⁴ and Ghalib Alkhatib^1*

Department of Microbiology and Immunology and Indiana University School of Medicine, 635 Barnhill Drive, Room 420, Indianapolis, Indiana 46202, and the Walther Cancer Institute, Indianapolis, Indiana 46208,¹ Department of Neurology, Nanjing Medical University, Nanjing, Jiangsu Province, China 210029,² INSERM, U822, IFR69, Le Kremlin-Bicêtre F-94276, France; Univ. Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre F-94275, France; and AP-HP, Hopital Bicêtre, Service de Santé Publique, Le Kremlin-Bicêtre F-94275, France,³ Hôpital Pitié Salpetrière et INSERM UR543 Bâtiment CERVI, 83 Bd. de l'Hôpital, 75013 Paris, France⁴

Received 7 January 2007/ Accepted 15 May 2007

Human immunodeficiency virus type 1 (HIV-1) infection of individuals carrying the two alleles of the CCR532 mutation (CCR5^–/–) has rarely been reported, but how the virus overcomes the CCR532 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 CCR532 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 CCR532 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 CCR532 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 CCR532 protein conferred resistance to primary X4 but not to lab-adapted X4 virus. These data provide strong support for the hypothesis that the CCR532 protein actively confers resistance to HIV-1 in vivo and suggest that the loss or reduction of CCR532 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 CCR532 protein.

Published ahead of print on 23 May 2007.

Contributed equally to the work.

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