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Journal of Virology, July 2004, p. 7602-7609, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7602-7609.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

PSC-RANTES Blocks R5 Human Immunodeficiency Virus Infection of Langerhans Cells Isolated from Individuals with a Variety of CCR5 Diplotypes

Tatsuyoshi Kawamura,1 Shannon E. Bruce,2 Awet Abraha,3 Makoto Sugaya,1 Oliver Hartley,4 Robin E. Offord,4 Eric J. Arts,3 Peter A. Zimmerman,2 and Andrew Blauvelt1*

Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland,1 Center for Global Health and Diseases,2 Department of Medicine, Case Western Reserve University, Cleveland, Ohio,3 Departement de Biochime Medicale, Universite de Geneve, Geneva, Switzerland4

Received 9 January 2004/ Accepted 17 March 2004

Topical microbicides that effectively block interactions between CCR5+ immature Langerhans cells (LC) residing within genital epithelia and R5 human immunodeficiency virus (HIV) may decrease sexual transmission of HIV. Here, we investigated the ability of synthetic RANTES analogues (AOP-, NNY-, and PSC-RANTES) to block R5 HIV infection of human immature LC by using a skin explant model. In initial experiments using activated peripheral blood mononuclear cells, each analogue compound demonstrated marked antiviral activity against two R5 HIV isolates. Next, we found that 20-min preincubation of skin explants with each RANTES analogue blocked R5 HIV infection of LC in a dose-dependent manner (1 to 100 nM) and that PSC-RANTES was the most potent of these compounds. Similarly, preincubation of LC with each analogue was able to block LC-mediated infection of cocultured CD4+ T cells. Competition experiments between primary R5 and X4 HIV isolates showed blocking of R5 HIV by PSC-RANTES and no evidence of increased propagation of X4 HIV, data that are consistent with the specificity of PSC-RANTES for CCR5 and the CCR5+ CXCR4– phenotype of immature LC. Finally, when CCR5 genetic polymorphism data were integrated with results from the in vitro LC infection studies, PSC-RANTES was found to be equally effective in inhibiting R5 HIV in LC isolated from individuals with CCR5 diplotypes known to be associated with low, intermediate, and high cell surface levels of CCR5. In summary, PSC-RANTES is a potent inhibitor of R5 HIV infection in immature LC, suggesting that it may be useful as a topical microbicide to block sexual transmission of HIV.

* Corresponding author. Present address: Oregon Health & Sciences University, 3710 SW U.S. Veterans Hospital Rd., Mail Code R&D 55, Portland, OR 97239. Phone: (503) 273-5112. Fax: (503) 273-5351. E-mail: blauvela{at}ohsu.gov.

Journal of Virology, July 2004, p. 7602-7609, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7602-7609.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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