The Toll-like receptor 7 (TLR7) agonist, imiquimod, and the TLR9 agonist, CpG ODN, induce antiviral cytokines and chemokines but do not prevent vaginal transmission of simian immunodeficiency virus when applied intravaginally to rhesus macaques.
The initial host response to viral infection occurs after Toll-like receptors (TLRs) on dendritic cells (DC) are stimulated by viral nucleic acids (double-stranded RNA, single-stranded RNA) and alpha interferon (IFN-alpha) and IFN-beta are produced. We hypothesized that pharmacologic induction of innate antiviral responses in the cervicovaginal mucosa by topical application of TLR agonists prior to viral exposure could prevent or blunt vaginal transmission of simian immunodeficiency virus (SIV). To test this hypothesis, we treated rhesus monkeys intravaginally with either the TLR9 agonist, CpG oligodeoxynucleotides (ODN), or the TLR7 agonist, imiquimod. Both immune modifiers rapidly induced IFN-alpha and other antiviral effector molecules in the cervicovaginal mucosa of treated animals. However, both CpG ODN and imiquimod also induced proinflammatory cytokine expression in the cervicovaginal mucosa. In the vaginal mucosa of imiquimod-treated monkeys, we documented a massive mononuclear cell infiltrate consisting of activated CD4(+) T cells, DC, and beta-chemokine-secreting cells. After vaginal SIV inoculation, all TLR agonist-treated animals became infected and had plasma vRNA levels that were higher than those of control monkeys. We conclude that induction of mucosal innate immunity including an IFN-alpha response is not sufficient to prevent sexual transmission of human immunodeficiency virus.
Wang
Yichuan
Y
California National Primate Research Center, University of California-Davis, Davis, California 95616, USA.
Abel
Kristina
K
Lantz
Katherine
K
Krieg
Arthur M
AM
McChesney
Michael B
MB
Miller
Christopher J
CJ
D000282:Administration, Intravaginal; D000634:Aminoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D015226:Dinucleoside Phosphates; D005260:Female; D000077271:Imiquimod; D008253:Macaca mulatta; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000635:transmission*; D014621:Vagina / Q000821:virology*
D000634:Aminoquinolines; D018925:Chemokines; D016207:Cytokines; D015226:Dinucleoside Phosphates; D000077271:Imiquimod; D009838:Oligodeoxyribonucleotides; C015772:CpG dinucleotide