**humanized mouse model to demonstrate that the number of target cells present in the reproductive tract are the predominant determinant in the outcome of exposure

**humanized mouse model to demonstrate that the number of target cells present in the reproductive tract are the predominant determinant in the outcome of exposure.42 Viral load was also an important criterion. simultaneously induce biologically active interferon- (IFN) antiviral Rabbit Polyclonal to MITF responses following exposure to HIV-1 that act Acotiamide hydrochloride trihydrate to protect the epithelial Acotiamide hydrochloride trihydrate tight junction barrier. The innate antiviral response was directly induced by HIV-1 envelope glycoprotein gp120 and addition of gp120 neutralizing antibody inhibited IFN production. Interferon- was induced by gp120 in upper GECs through Toll-like receptor 2 signaling and required presence of heparan sulfate on epithelial cell surface. The induction of IFN was dependent upon activation of transcription factor IRF3 (interferon regulatory factor 3). The IFN was biologically active, had a protective effect on epithelial tight junction barrier and was able to inhibit HIV-1 infection in TZM-bl indicator cells and HIV-1 replication in T cells. This is the first report that recognition of HIV-1 by upper GECs leads to induction of innate antiviral pathways. This could explain the overall low infectivity of HIV-1 in the FRT and could be exploited for Acotiamide hydrochloride trihydrate HIV-1 prophylaxis. Introduction Almost 70% of HIV infection occurs via sexual transmission in the intestinal or genital tract. Globally, women constitute more than half of 36.9 million HIV-infected individuals. HIV and AIDS are the leading causes of death worldwide among women of reproductive age. Clinical and experimental studies indicate that HIV can be transmitted through both the upper (oviduct, uterus and endocervix) and lower (ectocervix, vagina) genital tract. In particular, the transformation zone in the cervix is considered to be a highly susceptible site because of the presence of a large number of target cells in the lamina propria, below the epithelium.1 However, despite the relatively large surface area available for HIV-1 exposure and the higher incidence in women, the overall transmission in female reproductive tract (FRT) is relatively inefficient, estimated at 1:200 to 1 1:2000 per coital act, indicating that the FRT provides a significant barrier to HIV transmission.2 Following HIV-1 exposure, the acute events that determine the outcome of the interaction with the virus in the FRT are still not well understood. HIV needs to cross the epithelial lining of the genital mucosa in order to establish infection in the female genital tract. There is general consensus that the epithelial cells themselves do not get infected.1 However, there is increasing evidence that they play a key role as sensors and first responders for the host innate immune system, in addition to forming a physical and functional barrier against microorganisms.3 The upper genital epithelial cells (GECs) are dynamically active cells that display a carefully orchestrated response to external stimuli. They perform a multitude of tasks in encounters with pathogens, including induction of innate responses, as well as relaying signals to activate other cells of the innate and adaptive immune system. Both the upper and lower genital tract epithelium have been shown to express antimicrobial peptides as well as a repertoire of pathogen Acotiamide hydrochloride trihydrate pattern recognition receptors like Toll-like receptors (TLRs) that allows them to respond to a wide array of pathogens and initiate innate and adaptive responses.4 We and others have reported the induction of innate antiviral responses in upper GEC cultures following treatment with TLR ligands, resulting in decreased HSV-2 replication. The TLR3 ligand polyinosinic:polycytidylic acid (poly I:C) was shown to induce the greatest antiviral effect, but this was accompanied with enhanced production of inflammatory cytokines.5,6 The antiviral effect Acotiamide hydrochloride trihydrate by upper GECs was mediated by production of interferon- (IFN) in response to TLR ligands. Other studies have also reported production of interferon-stimulated factors such as MyxA, 25-oligoadenylate synthetase (OAS) and inducible nitric oxide synthase that have direct antiviral effects in primary cultures of endometrial epithelial cells as well as cervical and cervicovaginal cell lines.6,7 Type I interferons (IFNs) play a mixed role in HIV-1 infection. In general, production of.