Thursday, November 21, 2024
11/21/2024
ABSTRACT This proposal is a multi PI proposal that aims to understand how antiviral proteins limit host range. Prior work has demonstrated that type I interferon (IFN) induced proteins limit primate lentivirus replication in natural and non-natural hosts. Indeed, our previous studies have led to the discovery of antiviral interferon stimulated genes (ISGs), elucidated their mechanism of action and uncovered ways in which primate lentiviruses evolve evade or counteract antiviral proteins. Additionally, we have exploited this knowledge to generate novel chimeric viruses that better represent the HIV-1 strains circulating in humans for use in non-human primate models, including a minimally modified HIV-1 strain (stHIV) that can cause AIDS in pigtail macaques when CD8+ cells are transiently depleted during the acute infection. In this new proposal, we will explore the role of type I IFN and novel antiviral ISGs in limiting primate lentivirus replication in vitro and in vivo. Specific Aim 1 will explore the mechanism of action of antiviral ISGs affecting viral entry. Using a CRISPR screen, we have found novel ISGs whose expression appears to inhibit HIV-1 infection, specifically at the virus entry step. Knockout of one of these genes enhances HIV-1 infection in a manner that varies dramatically according to the particular strain from which the Env protein is derived. Importantly, the magnitude of effect of the ISG on HIV-1 infection mediated by a particular Env variant correlates with the sensitivity of a virus carrying that Env variant to inhibition by type I IFN. We will determine the molecular details of the how IFN/ISGs inhibits HIV-1 entry by elucidating viral and host determinants of inhibition, across cell types and species, and use imaging and other approaches to determine how inhibition affects incoming viron fate. We will also determine how novel ISGs contribute to the differential IFN sensitivity of primary transmitted founder and chronic HIV-1 strains and adapted/unadapted SHIVs. In Specific Aim 2, we will use newly developed, more effective methods to perturb type I IFN in macaques to determine the effect of IFN on primate lentivirus replication therein. In particular, we will determine the effect of type I IFN blockade on stHIV replication and clinical course in pigtail macaques. We will also use SHIV to determine whether HIV-1 Env variants that exhibit differential type I IFN sensitivity in vitro, also do so in vivo. Finally, we will determine how type I IFN affects SHIV dissemination and competitiveness use barcoded SHIVs, bearing IFN/ISG-sensitive and resistant HIV-1 Env proteins, defined in Aim 1, by determining how efficiently each SHIV disseminates in macaques in the presence and absence of type I IFN blockade.
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