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Journal of Virology, June 2005, p. 6848-6858, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6848-6858.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Induction of Murine Mucosal CCR5-Reactive Antibodies as an Anti-Human Immunodeficiency Virus Strategy

C. Barassi,1 E. Soprana,2 C. Pastori,1 R. Longhi,3 E. Buratti,4 F. Lillo,1 C. Marenzi,3,{dagger} A. Lazzarin,1 A. G. Siccardi,2,5 and L. Lopalco1*

Infectious Diseases Clinic,1 DIBIT, San Raffaele Scientific Institute, Milano, Italy,2 Istituto Riconoscimento Molecolare, CNR, Milano, Italy,3 International Center for Genetic Engineering, Trieste, Italy,4 Department of Biology and Genetics, University of Milano, Milano, Italy5

Received 14 October 2004/ Accepted 20 January 2005

The genital mucosa is the main site of initial human immunodeficiency virus type 1 (HIV-1) contact with its host. In spite of repeated sexual exposure, some individuals remain seronegative, and a small fraction of them produce immunoglobulin G (IgG) and IgA autoantibodies directed against CCR5, which is probably the cause of the CCR5-minus phenotype observed in the peripheral blood mononuclear cells of these subjects. These antibodies recognize the 89-to-102 extracellular loop of CCR5 in its native conformation. The aim of this study was to induce infection-preventing mucosal anti-CCR5 autoantibodies in individuals at high risk of HIV infection. Thus, we generated chimeric immunogens containing the relevant CCR5 peptide in the context of the capsid protein of Flock House virus, a presentation system in which it is possible to engineer conformationally constrained peptide in a highly immunogenic form. Administered in mice via the systemic or mucosal route, the immunogens elicited anti-CCR5 IgG and IgA (in sera and vaginal fluids). Analogous to exposed seronegative individuals, mice producing anti-CCR5 autoantibodies express significantly reduced levels of CCR5 on the surfaces of CD4+ cells from peripheral blood and vaginal washes. In vitro studies have shown that murine IgG and IgA (i) specifically bind human and mouse CD4+ lymphocytes and the CCR5-transfected U87 cell line, (ii) down-regulate CCR5 expression of CD4+ cells from both humans and untreated mice, (iii) inhibit Mip-1ß chemotaxis of CD4+ CCR5+ lymphocytes, and (iv) neutralize HIV R5 strains. These data suggest that immune strategies aimed at generating anti-CCR5 antibodies at the level of the genital mucosa might be feasible and represent a strategy to induce mucosal HIV-protective immunity.

* Corresponding author. Mailing address: Infectious Diseases Clinic, San Raffaele Scientific Institute, via S. D'Ancona 20, 20127 Milano, Italy. Phone: 011.39.02.2643.7936. Fax: 011.39.02.2643.7989. E-mail: lopalco.lucia{at}hsr.it.

{dagger} Present address: Department of Surgery, Duke University Medical Center, Durham, North Carolina.

Journal of Virology, June 2005, p. 6848-6858, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6848-6858.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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