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Kinetics of early innate immune activation during HIV-1 infection of humanized mice

Skelton, JK; Ortega-Prieto, AM; Kaye, S; Jimenez-Guardeño, JM; Turner, J; Malim, MH; Towers, GJ; (2019) Kinetics of early innate immune activation during HIV-1 infection of humanized mice. Journal of Virology 10.1128/JVI.02123-18. (In press). Green open access

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Abstract

Human immunodeficiency virus type-1 (HIV-1) infection is associated with aberrant immune activation, however, most model systems for HIV-1 have been used during established infection. Here, we utilize ultra-sensitive HIV-1 quantification to delineate early events during the HIV-1 eclipse, burst and chronic phases of HIV-1 infection in humanized mice. We show that very early in infection, HIV-1 suppresses peripheral type I interferon (IFN) and interferon-stimulated gene (ISG) responses, including the HIV-1 restriction factor IFI44. At the peak of innate immune activation, prior to CD4 T cell loss, HIV-1 infection differentially affects peripheral and lymphoid TLR expression profiles in T cells and macrophages. This results in a trend towards an altered activation of NFκB, TBK1 and IRF3. The subsequent type I and III IFN responses result in preferential induction of peripheral ISG responses. Following this initial innate immune activation, peripheral expression of the HIV-1 restriction factor SAMHD1 returns to levels below those observed in uninfected mice, suggesting that HIV-1 interferes with their basal expression. However, peripheral cells, still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISG in response to IFN. This demonstrates the highly dynamic nature of very early HIV-1 infection and suggests that blocks to the induction of HIV-1 restriction factors contribute to the establishment of viral persistence.IMPORTANCE Human immunodeficiency virus (HIV)-1 infection is restricted to humans and some non-human primates (e.g. chimpanzee, gorilla). Alternative model systems based on SIV infection of macaques are available but do not recapitulate all aspects of HIV-1 infection and disease. Humanized mice, which contain a human immune system, can be used to study HIV-1 but only limited information on early events and immune responses are available to date. Here, we describe very early immune responses to HIV-1 and demonstrate a suppression of cell-intrinsic innate immunity. Furthermore, we show that HIV-1 infection interacts differently with innate immune responses in blood and lymphoid organs.

Type: Article
Title: Kinetics of early innate immune activation during HIV-1 infection of humanized mice
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1128/JVI.02123-18
Publisher version: https://doi.org/10.1128/JVI.02123-18
Language: English
Additional information: This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10070438
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