JVI Accepts, published online ahead of print on 11 March 2009

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J. Virol. doi:10.1128/JVI.00055-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Selection of SHIV resistant to a vaginal microbicide in macaques

Dawn M. Dudley, Jennifer L. Wentzel, Matthew S. Lalonde, Ronald S. Veazey, and Eric J. Arts^*

Department of Molecular Biology and Microbiology, Division of Infectious Diseases, Department of Medicine, Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106; Department of Pathology, Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, LA

^* To whom correspondence should be addressed. Email: eja3{at}case.edu.

PSC-RANTES binds to CCR5, inhibits HIV-1 entry, and has been shown to protect rhesus macaques as a vaginal microbicide from SHIV_SF162-p3 infection in a dose-dependent manner. In this study, env gene sequences from SHIV_SF162-p3-infected rhesus macaques treated with PSC-RANTES were analyzed for possible drug escape variants. Two specific mutations located in the V3 region of gp120 (K315R) and C-helical domain of gp41 (N640D) were identified in a macaque (m584) pre-treated with a 100 µM dose of PSC-RANTES. These two env mutations were found throughout infection (through week 77) but were only found at low frequencies in the inoculating SHIV_SF162-p3 stock and in the other SHIV_SF162-p3-infected macaques. HIV-1 env genes from the m584 macaque and from inoculating SHIV_SF162-p3 were cloned into an HIV-1 backbone. Increases in IC₅₀ values to PSC-RANTES with env_m584 was modest (7-fold) and most pronounced in cells expressing rhesus macaque as compared to human CCR5. Nonetheless, virus harboring the env_m584, unlike inoculating env_p3, could replicate even at the highest tissue culture PSC-RANTES concentrations (100 nM). Dual virus competitions revealed a dramatic increase in fitness of chimeric virus containing the env_m584 (K315R/N640D) over that containing the env_p3, but again, only in rhesus CCR5-expressing cells. This study is the first to describe the immediate selection and infection of a drug-resistant SHIV variant in the face of a protective vaginal microbicide, PSC-RANTES. This rhesus CCR5-specific/PSC-RANTES-resistance selection is particularly alarming given the relative homogeneity of the SHIV_SF162-p3 stock as compared to the potential exposure to a heterogeneous HIV-1 population in human transmission.