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

Abstract

Summary Despite 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.

Early transcriptome profile of goat peripheral blood mononuclear cells (PBMCs) infected with peste des petits ruminant's vaccine virus (Sungri/96) revealed induction of antiviral response in an interferon independent manner

“…TREX1 may act as negative regulator of induction of type I interferons in PPRV infected PBMCs. Similar effect of TREX1 was observed recently in HIV infection (Wheeler et al, 2016). TREX1 could be one of the breaks, having inhibitory effect on type I IFN signaling pathway, allowing virus to replicate in the initial stages of the infection.…”

Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer

“…Humanized mice were generated from NOD/SCID/IL2rγ null (NSG) mice (Jackson Laboratories) as previously described 27,53 . Fresh human CB and fetal thymi were obtained from Sun Yat-Sen Memorial Hospital, according to guidelines approved by the hospital Ethics Boards and Clinical Research Committee.…”

Human Endogenous Retroviruses (HERVs): Shaping the Innate Immune Response in Cancers

“…Regulation mechanisms exist, such as 3 repair exonuclease 1 (TREX1), a 3 →5 DNA exonuclease that degrades retroviral DNA, thus preventing their accumulation [44]. TREX1 knock down increases type I IFN production after HIV infection in mucosal cells [45]. Albeit performed in mice, these experiments suggest that similar mechanisms could exist for modulating immune activation from nucleic acid sensing.…”