Quantification of Poly(I:C)-Mediated Protection against Genital Herpes Simplex Virus Type 2 Infection

Abstract

Alternative strategies for controlling the growing herpes simplex virus type 2 (HSV-2) epidemic are needed. A novel class of immunomodulatory microbicides has shown promise as antiherpetics, including intravaginally applied CpG-containing oligodeoxynucleotides that stimulate toll-like receptor 9 (TLR9). In the current study, we quantified protection against experimental genital HSV-2 infection provided by an alternative nucleic acid-based TLR agonist, polyinosine-poly(C) (PIC) (TLR3 agonist). Using a protection quantification paradigm, groups of mice were PIC treated and then subdivided into groups challenged with escalating doses of HSV-2. Using this paradigm, a temporal window of PIC efficacy for single applications was defined as 1 day prior to (prophylactic) through 4 h after (therapeutic) viral challenge. PIC treatment within this window protected against 10-fold-higher HSV-2 challenges, as indicated by increased 50% infectious dose values relative to those for vehicle-treated controls. Disease resolution and survival were significantly enhanced by repetitive PIC doses. Using optimal PIC regimens, cytokine induction was evaluated in murine vaginal lavages and in human vaginal epithelial cells. Similar induction patterns were observed, with kinetics that explained the limited durability of PIC-afforded protection. Daily PIC delivery courses did not generate sustained cytokine levels in murine vaginal fluids that would be indicative of local immunotoxicity. No evidence of immunotoxicity was observed in selected organs that were analyzed following repetitive vaginal PIC doses. Animal and in vitro data indicate that PIC may prove to be a valuable preventative microbicide and/or therapeutic agent against genital herpes by increasing resistance to HSV-2 and enhancing disease resolution following a failure of prevention.

Polyinosinic-Polycytidylic Acid Treatment of Friend Retrovirus-Infected Mice Improves Functional Properties of Virus-Specific T Cells and Prevents Virus-Induced Disease

“…4). Several other studies with nonretroviruses have shown that poly(I:C) has an antiviral effect in vivo (39)(40)(41)(42)(43). An induction of IFN-a and antiviral enzymes was observed, but the effect of the TLR ligand on the virus-specific adaptive immune response was not investigated in any of these studies.…”

“…However, little is known about the antiviral effect of poly(I:C) in retroviral infections (39)(40)(41)(42)(43). In addition, none of the previous studies in any infection model investigated the underlying mechanisms of the antiviral activity of poly(I:C) in vivo.…”

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

“…Thus, poly(I:C) might have most potential as a topical strategy that could be applied immediately within 24 h after exposure to curb local spread. In addition, the ability of TLR3 ligation to limit herpes simplex virus infection (4,28,33,63,76) would also help to control the spread of HIV (11).…”

HSV-2: in pursuit of a vaccine

“…Interestingly, most host mutations associated with fatal HSV in childhood occur at loci classically associated with innate immunity, such as TLR3 (57) and UNC93B1 (59), although some mutations associated with severe HSV are in genes involved in both innate and acquired immune responses (e.g., STAT1), reflecting a complex codependence and interaction between these pathways (60). Although innate immune system agonists can lead to profound, local HSV resistance (61,62), these interventions are outside the realm of classic vaccinology. Single nucleotide polymorphisms in TLR2 are associated with more frequent HSV shedding and genital lesions (63), which suggests that there may be a host genetic contribution to the wide heterogeneity of clinical HSV presentation.…”