An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection.
Herpes simplex virus 2 (HSV-2) infection causes significant morbidity and is an important cofactor for the transmission of HIV infection. A microbicide to prevent sexual transmission of HSV-2 would contribute substantially to controlling the spread of HIV and other infections. Because RNA interference (RNAi) provides effective antiviral defence in plants and other organisms, several studies have focused on harnessing RNAi to inhibit viral infection. Here we show that vaginal instillation of small interfering RNAs (siRNAs) targeting HSV-2 protects mice from lethal infection. siRNAs mixed with lipid are efficiently taken up by epithelial and lamina propria cells and silence gene expression in the mouse vagina and ectocervix for at least nine days. Intravaginal application of siRNAs targeting the HSV-2 UL27 and UL29 genes (which encode an envelope glycoprotein and a DNA binding protein, respectively) was well tolerated, did not induce interferon-responsive genes or cause inflammation, and protected mice when administered before and/or after lethal HSV-2 challenge. These results suggest that siRNAs are attractive candidates for the active component of a microbicide designed to prevent viral infection or transmission.
Palliser
Deborah
D
CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts 02115, USA.
Chowdhury
Dipanjan
D
Wang
Qing-Yin
QY
Lee
Sandra J
SJ
Bronson
Roderick T
RT
Knipe
David M
DM
Lieberman
Judy
J
D000282:Administration, Intravaginal; D000818:Animals; D002460:Cell Line; D002584:Cervix Uteri / Q000821:virology; D005260:Female; D020868:Gene Silencing; D020043:Genes, Essential / Q000235:genetics; D005814:Genes, Viral / Q000235:genetics; D006558:Herpes Genitalis / Q000150:complications / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D007249:Inflammation; D007372:Interferons / Q000502:physiology; D008081:Liposomes / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors; D014621:Vagina / Q000821:virology; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication
D008081:Liposomes; D034741:RNA, Small Interfering; C413084:UL29 protein, Herpes simplex virus type 2; D014764:Viral Proteins; D007372:Interferons