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Journal of Virology, May 2009, p. 5067-5076, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.00055-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Selection of a Simian-Human Immunodeficiency Virus Strain Resistant to a Vaginal Microbicide in Macaques{triangledown} ,{dagger}

Dawn M. Dudley,1,2 Jennifer L. Wentzel,2 Matthew S. Lalonde,2,3 Ronald S. Veazey,4 and Eric J. Arts1,2,3*

Department of Molecular Biology and Microbiology,1 Division of Infectious Diseases, Department of Medicine,2 Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106,3 Department of Pathology, Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana4

Received 9 January 2009/ Accepted 1 March 2009

PSC-RANTES binds to CCR5, inhibits human immunodeficiency virus type 1 (HIV-1) entry, and has been shown as a vaginal microbicide to protect rhesus macaques from a simian-human immunodeficiency virus chimera (SHIVSF162-p3) infection in a dose-dependent manner. In this study, env gene sequences from SHIVSF162-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) pretreated with a 100 µM dose of PSC-RANTES. These two env mutations were found throughout infection (through week 77) but were found at only low frequencies in the inoculating SHIVSF162-p3 stock and in the other SHIVSF162-p3-infected macaques. HIV-1 env genes from macaque m584 (envm584) and from inoculating SHIVSF162-p3 (envp3) were cloned into an HIV-1 backbone. Increases in 50% inhibitory concentrations to PSC-RANTES with envm584 were modest (sevenfold) and most pronounced in cells expressing rhesus macaque CCR5 as compared to human CCR5. Nonetheless, virus harboring envm584, unlike inoculating virus envp3, 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 envm584 (K315R/N640D) over that containing envp3, 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 SHIVSF162-p3 stock compared to the potential exposure to a heterogeneous HIV-1 population in human transmission.

* Corresponding author: Mailing Address: Division of Infectious Diseases, BRB 1029, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Phone: (216) 368-8904. Fax: (216) 368-2034. E-mail: eja3{at}case.edu

{triangledown} Published ahead of print on 11 March 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, May 2009, p. 5067-5076, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.00055-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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