TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice

• CD4-aptamer-siRNA chimeras knock down TREX1 in CD4+ cells in the genital mucosa
• Knocking down TREX1 increases type I IFN production by HIV-infected mucosal cells
• TREX1 knockdown in genital mucosa suppresses HIV infection through IFN induction
• TREX1 knockdown in the genital tract delays HIV transmission in vivo

SummaryDespite their antiviral effect, the in vivo effect of interferons on HIV transmission is difficult to predict, because interferons also activate and recruit HIV-susceptible cells to sites of infection. HIV does not normally induce type I interferons in infected cells, but does if TREX1 is knocked down. Here, we investigated the effect of topical TREX1 knockdown and local interferon production on HIV transmission in human cervicovaginal explants and humanized mice. In explants in which TREX1 was knocked down, HIV induced interferons, which blocked infection. In humanized mice, even though TREX1 knockdown increased infiltrating immune cells, it delayed viral replication for 3–4 weeks. Similarly intravaginal application of type I interferons the day before HIV infection induced interferon responsive genes, reduced inflammation, and decreased viral replication. However, intravenous interferon enhanced inflammation and infection. Thus, in models of human sexual transmission, a localized interferon response inhibits HIV transmission but systemic interferons do not.

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