title: Selection of a simian-human immunodeficiency virus strain resistant to a vaginal microbicide in macaques.
abstract: 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 (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) pretreated with a 100 microM 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 SHIV(SF162-p3) stock and in the other SHIV(SF162-p3)-infected macaques. HIV-1 env genes from macaque m584 (env(m584)) and from inoculating SHIV(SF162-p3) (env(p3)) were cloned into an HIV-1 backbone. Increases in 50% inhibitory concentrations to PSC-RANTES with env(m584) were modest (sevenfold) and most pronounced in cells expressing rhesus macaque CCR5 as compared to human CCR5. Nonetheless, virus harboring env(m584), unlike inoculating virus 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 env(m584) (K315R/N640D) over that containing 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 compared to the potential exposure to a heterogeneous HIV-1 population in human transmission.
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Dudley
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wentzel
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Lalonde
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Arts
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000494:pharmacology*; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D005260:Female; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008253:Macaca mulatta / Q000821:virology; D009154:Mutation; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000235:genetics; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000235:genetics*; D014621:Vagina / Q000821:virology*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D018946:Chemokine CCL5; C492865:RANTES, N(alpha)-(n-nonanoyl)-desSer(1)-(thioproline(2),cyclohexylglycine(3))-; D012367:RNA, Viral; D054299:env Gene Products, Human Immunodeficiency Virus