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J. Virol. doi:10.1128/JVI.00068-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

CCR532 Protein Expression and Stability are Critical for Resistance to HIV-1 in vivo

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

^* To whom correspondence should be addressed. Email: galkhati{at}iupui.edu.

	Abstract

HIV-1 infection of CCR5-/- individuals 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 form HIV^-CCR5-/- peripheral blood mononuclear cells (PBMCs) showed lower 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. Expression of adenovirus 5 (Ad5)-encoded CCR532 protein restored the protective effect in PBMCs from three HIV⁺ CCR5-/- 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 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 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.

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